endothelin-1 and Acute-Kidney-Injury

The role of the vasoactive peptide endothelin-1 (ET-1) in renal injury is not fully understood. In this review, we examine the genetic models available to understand the autocrine/paracrine mechanisms by which ET-1 leads to renal injury and propose the working hypothesis that endothelium-derived ET-1 induces renal injury by initiating renal tubular apoptosis in a paracrine manner.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Disease Progression; Endothelin-1; Endothelium, Vascular; Kidney Tubules; Mice; Mice, Knockout; Models, Cardiovascular; Paracrine Communication

Smooth muscle contraction is activated primarily by phosphorylation at Ser19 of the regulatory light chain subunits (LC20) of myosin II, catalysed by Ca(2+)/calmodulin-dependent myosin light chain kinase. Ca(2+)-independent contraction can be induced by inhibition of myosin light chain phosphatase, which correlates with diphosphorylation of LC20 at Ser19 and Thr18, catalysed by integrin-linked kinase (ILK) and zipper-interacting protein kinase (ZIPK). LC20 diphosphorylation at Ser19 and Thr18 has been detected in mammalian vascular smooth muscle tissues in response to specific contractile stimuli (e.g. endothelin-1 stimulation of rat renal afferent arterioles) and in pathophysiological situations associated with hypercontractility (e.g. cerebral vasospasm following subarachnoid hemorrhage). Comparison of the effects of LC 20 monophosphorylation at Ser19 and diphosphorylation at Ser19 and Thr18 on contraction and relaxation of Triton-skinned rat caudal arterial smooth muscle revealed that phosphorylation at Thr18 has no effect on steady-state force induced by Ser19 phosphorylation. On the other hand, the rates of dephosphorylation and relaxation are significantly slower following diphosphorylation at Thr18 and Ser19 compared to monophosphorylation at Ser19. We propose that this diphosphorylation mechanism underlies the prolonged contractile response of particular vascular smooth muscle tissues to specific stimuli, e.g. endothelin-1 stimulation of renal afferent arterioles, and the vasospastic behavior observed in pathological conditions such as cerebral vasospasm following subarachnoid hemorrhage and coronary arterial vasospasm. ILK and ZIPK may, therefore, be useful therapeutic targets for the treatment of such conditions.

Topics: Acute Kidney Injury; Animals; Catalysis; Coronary Vasospasm; Death-Associated Protein Kinases; Endothelin-1; Humans; Hypertension; Microcirculation; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Myosin Type II; Myosin-Light-Chain Kinase; Myosin-Light-Chain Phosphatase; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Renal Circulation; Vasoconstriction; Vasospasm, Intracranial

There is an increasing number of clinical studies suggesting that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, it could potentially be a leading cause of, or contributor to, end-stage renal disease. Insights into the natural history of AKI and potential mechanisms for disease progression can be gleaned from experimental studies. Although such studies underscore the principle that AKI can 'heal with defects', whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated, which may retard or prevent severe chronic kidney disease. Furthermore, the onset of acute uremia per se may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Disease Models, Animal; Disease Progression; Endothelin-1; Glucocorticoids; Humans; Kidney; Nephritis, Interstitial; Renal Insufficiency, Chronic; Renal Replacement Therapy; Reperfusion Injury; Uremia

Endothelin (ET) has been implicated in the pathogenesis of several cardiovascular disorders because of its powerful vasoconstrictor and growth-promoting properties. The ET family consists of three isoforms, ET-1, ET-2 and ET-3. ET-1 appears to be the predominant member of the family generated by vascular endothelial cells. In view of the multiple cardiovascular actions of ET-1, there has been much interest in its contribution to the pathophysiology of hypertension and arteriosclerosis. We have been investigating the roles of ET(A) and ET(B) receptors in ET-1-related cardiovascular diseases using subtype-selective ET receptor antagonists and ET(B) receptor-deficient animals. Our studies have demonstrated that ET-1 overproduction and ET(A)-mediated ET-1 actions seem to play a crucial role in the development of several types of hypertensive and post-ischemic diseases. On the other hand, ET-1 biosynthesis and release are regulated at the transcriptional level, and various endogenous substances are known to stimulate ET-1 gene expression by DNA binding of transcription factors. We and others have recently demonstrated that nuclear factor-kappaB (NF-kappaB), a transcription factor with a pivotal role in inducing genes involved in immune, inflammatory and stress responses, is responsible for endothelial ET-1 production. In in vivo studies, agents that can inhibit the NF-kappaB activation improved the development of ET-1-related cardiovascular diseases. Thus, NF-kappaB inhibition may be a pertinent treatment for ET-1 related diseases.

Topics: Acute Kidney Injury; Animals; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Humans; Hypertension; NF-kappa B; Nitric Oxide; Receptor, Endothelin A

Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ET(A) and ET(B) receptors, while constrictor effects are primarily transduced by ET(A) receptors, dual ET receptor blockade may be superior over selective ET(A) antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.

Topics: Acute Kidney Injury; Animals; Chronic Disease; Diabetic Nephropathies; Endothelin-1; Endothelins; Glomerulonephritis; Hepatorenal Syndrome; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Receptors, Endothelin

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kappaB (NF-kappaB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kappaB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.

Topics: Acute Kidney Injury; Animals; Blood Vessels; Cardiovascular Diseases; Endothelin-1; Humans; Hypertension; Hypertrophy; Ischemia; Kidney; Proteasome Endopeptidase Complex; Proteasome Inhibitors

Topics: Acute Kidney Injury; Angiotensin II; Animals; Endothelin-1; Endothelins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Nitric Oxide

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Disease Progression; Endothelin-1; Glomerular Filtration Rate; Humans; Kidney Tubular Necrosis, Acute; Mercuric Chloride; Vascular Resistance

Topics: Acute Kidney Injury; Adenosine; Endothelin-1; Humans; Interleukins; Leukotrienes; Nitric Oxide; Platelet Activating Factor; Renal Circulation; Sepsis; Tumor Necrosis Factor-alpha

Topics: Acute Kidney Injury; Endothelin-1; Humans; Ischemia; Neutrophils; Nitric Oxide; Renal Circulation; Reperfusion Injury

Extracorporeal shock wave lithotripsy (ESWL)-induced renal damage can occur as a result of multiple mechanisms. We have reported previously that Astragalus membranaceus, Salvia miltiorrhiza, a decoction of six drugs containing rhizoma Rehmanniae preparata and supplements of a few traditional Chinese medicinal herbs for invigorating the kidney and excreting calculus, have a protective effect on renal injury induced by high-energy shock waves (HESW) in rabbits. In this clinical study we further investigate the protective effects of these traditional Chinese herbs against renal damage induced by ESWL. Sixty consenting patients with renal calculus who underwent ESWL treatment were included and randomly assigned to the medication group or control group. Post-ESWL plasma nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), and serum tumor necrosis factor α (TNF-α) increased significantly in the controls (P < 0.05), while in the medication group, slightly but not significantly elevated levels of plasma ET-1, NO, and serum TNF-α were found. The difference between the groups was statistically significant (P < 0.05). The levels of superoxide dismutase (SOD) decreased gradually in the controls, reaching a trough 72 h after ESWL (P < 0.05), while in the treated group it was unchanged, and remained at a level higher versus the controls (P < 0.05). Plasma NO peaked twice by 72 h and at 1 week in the controls (P < 0.05). Urinary enzymes and β(2)-microglobulin increased significantly and peaked by 24 h and immediately after ESWL (P < 0.05). These values were greater in the controls, and the difference was statistically significant (P < 0.05). This study demonstrates that the preparations of traditional Chinese medicines for invigorating the kidney and excreting calculus can reduce renal tubular damage induced by ESWL, and can shorten the recovery time of renal tubules in human subjects.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Adult; Aged; beta 2-Microglobulin; Drugs, Chinese Herbal; Endothelin-1; Female; gamma-Glutamyltransferase; Humans; Kidney Calculi; Lithotripsy; Male; Malondialdehyde; Medicine, Chinese Traditional; Middle Aged; Nitric Oxide; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Young Adult

Scleroderma renal crisis (SRC) is a rare vascular complication of systemic sclerosis with substantial risks for end-stage renal disease and premature death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) have been identified as predictors for SRC. Here, we sought to determine their pathogenic significance for acute renal vascular injury potentially triggering kidney failure and malignant hypertension.. IgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signalling and mechanisms of receptor activation.. In myography experiments, patient IgG exerted vasoconstriction sensitive to inhibition of AT1R and ETAR. This relied on MEK-ERK signalling indicating functional relevance of anti-AT1R and anti-ETAR Abs. The contractile response to angiotensin II and endothelin-1 was amplified by patient IgG containing anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types which may enable the observed functional interrelation by direct structural interactions.. We provide experimental evidence that agonistic Abs may contribute to SRC. This effect is presumably related to direct receptor stimulation and additional allosteric effects, at least in heterodimeric receptor constellations. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Autoantibodies; Endothelin-1; Immunoglobulin G; Rats; Receptor, Endothelin A; Scleroderma, Localized; Vascular System Injuries

In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.

Topics: Acute Kidney Injury; Animals; Endothelin-1; Glycerol; Kidney; Myoglobin; Rats; Rats, Wistar; Rhabdomyolysis

Topics: Acute Kidney Injury; Animal Experimentation; Animals; Endothelin-1; Kidney; Rhabdomyolysis

The chemotherapeutic agent cisplatin accumulates in the kidney and induces acute kidney injury (AKI). Preclinical and clinical studies suggest that young female mice and women show greater recovery from cisplatin-AKI compared to young male mice and men. The endothelin (ET) and ET receptors are enriched in the kidney and may be dysfunctional in cisplatin-AKI; however, there is a gap in our knowledge about the putative effects of sex and cisplatin on the renal ET system. We hypothesized that cisplatin-AKI male and female mice will have increased expression of the renal ET system. As expected, all cisplatin-AKI mice had kidney damage and body weight loss greater than control mice. Cisplatin-AKI mice had greater cortical

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Endothelin-1; Female; Kidney; Male; Mice; Mice, Inbred C57BL

Discovering new nephroprotectants may provide therapeutic strategies in AKI.This study provides the first evidence that KLF11, a member of the Krüppel-like factor (KLF) family of proteins, protects against AKI.In the absence of KLF11, exaggerated induction of endothelin-1 and IL-6 occurs after ischemic renal injury and may contribute to worse AKI.

Topics: Acute Kidney Injury; Apoptosis Regulatory Proteins; Endothelin-1; Humans; Interleukin-6; Kidney; Kruppel-Like Transcription Factors; Protective Agents; Reperfusion Injury; Repressor Proteins

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. Despite advances in early diagnosis and management, the mortality rate of acute iTTP remains high in a large part of world where access to some of the most novel therapies is limited. To determine the role of plasma big endothelin-1 (bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients with iTTP on admission and during remission, as well as in healthy controls; moreover, the biological effect of ET-1 in thrombus formation was determined by a microfluidic assay. We show that plasma levels of bigET-1 were dramatically increased in patients with acute iTTP on admission, which was significantly decreased during clinical response/remission; elevated admission levels of plasma bigET-1 were associated with low estimated glomerular filtration rate, the need for intensive care unit admission or intubation, and in-hospital mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial cells in a microfluidic channel significantly accelerated the rate of thrombus formation under arterial flow. Our results demonstrate for the first time a potential role of measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity and risk of in-hospital mortality, which may help stratify patients for a more aggressive monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1, may result in acute renal injury in TTP patient, likely through its vasoconstriction and prothrombotic properties.

Topics: Acute Kidney Injury; ADAMTS13 Protein; Biomarkers; China; Early Diagnosis; Endothelin-1; Female; Hospital Mortality; Humans; Male; Middle Aged; Patient Selection; Plasma Exchange; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Risk Assessment; Severity of Illness Index

Although modulation of the vitamin D receptor (VDR) and endothelin-. Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6 mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration.. Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), and phosphorylated nuclear factor-kappa B (pNF-κB) content; and caspase-3 activity. They downregulated ET-1 and ET. These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this cross-talk.

Topics: Acute Kidney Injury; Animals; Cisplatin; Creatinine; Down-Regulation; Drug Synergism; Endothelin-1; Hydroxycholecalciferols; Male; Peptides, Cyclic; Rats, Sprague-Dawley; Receptor Cross-Talk; Receptors, Calcitriol; Receptors, Endothelin; Up-Regulation; Urea

Topics: Acute Kidney Injury; Cardiac Surgical Procedures; Endothelin-1; Endothelium, Vascular; Humans; Kinetics; Vascular Endothelial Growth Factor A

Acute kidney injury (AKI) after liver transplantation (LT) is a common event, but its pathogenesis remains unclear. The aim of this prospective study is to investigate the potential relationship between postreperfusion gene expression, serum mediators, and the onset of AKI after LT. Sixty-five consecutive patients undergoing LT were included in the study. Reverse transcription polymerase chain reaction (PCR) was performed on liver biopsies. Gene expression of 23 genes involved in ischemia/reperfusion injury (IRI) was evaluated. The serum concentrations of endothelin (ET)-1 and inflammatory cytokines were analyzed. AKI after LT developed in 21 (32%) recipients (AKI group). Reverse transcription PCR of reperfusion biopsy in the AKI group showed higher expression of several genes involved in IRI compared with the non-AKI group. Fold changes in the gene expression of ET-1, interleukin (IL) 18, and tumor necrosis factor α (TNF-α) were associated with creatinine peak value. AKI patients also had significantly higher ET-1, IL18, and TNF-α postoperative serum levels. Multivariate analysis showed that ET-1 (odds ratio [OR], 16.7; 95% confidence interval [CI], 3.34-83.42; P = 0.001) and IL18 (OR, 5.27; 95% CI, 0.99-27.82, P = 0.048) serum levels on postoperative day 1 were independently predictive of AKI. Receiver operating characteristic analysis demonstrated that the combination of biomarkers ET-1+IL18 was highly predictive of AKI (area under the receiver operating characteristic curve, 0.91; 95% CI, 0.83-0.99). Early allograft dysfunction and chronic kidney disease stage ≥ 2 occurred more frequently in AKI patients. These results suggest that the graft itself, rather than intraoperative hemodynamic instability, plays a main role in AKI after LT. These data may have mechanistic and diagnostic implications for AKI after LT. Liver Transplantation 24 922-931 2018 AASLD.

Topics: Acute Kidney Injury; Adult; Aged; Allografts; Biomarkers; Biopsy; Creatinine; Endothelin-1; Female; Gene Expression Profiling; Graft Rejection; Humans; Interleukin-18; Liver; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of tuberous sclerosis complex 1 (TSC1), an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1

Topics: Acute Kidney Injury; Animals; Apoptosis; Endothelin-1; Female; Fibroblasts; Immunosuppressive Agents; Kidney; Lipopolysaccharides; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Signal Transduction; Sirolimus; Tuberous Sclerosis Complex 1 Protein

The only curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). PEA requires cardiopulmonary bypass (CPB) which is associated with a high acute kidney injury (AKI) risk. Circulating endothelin-1 (ET-1) levels are elevated in CTEPH, and ET-1 plays a pivotal role in AKI. Because AKI is burdened by high morbidity and mortality, we aimed to evaluate the association between preoperative ET-1 and the risk to develop AKI in CTEPH individuals who undergo PEA. We also evaluated the association of AKI and ET-1 with kidney function and mortality at 1 year after PEA.. In 385 consecutive patients diagnosed with CTEPH who underwent PEA at the Foundation IRCC Policlinico San Matteo (Pavia, Italy) from January 2009 to April 2015, we assessed preoperative circulating ET-1 by ELISA and identified presence of AKI based on 2012 KDIGO criteria.. AKI occurred in 26.5% of the 347 patients included in the analysis, and was independently associated with preoperative ET-1 (p = 0.008), body mass index (BMI) (p = 0.022), male gender (p = 0.005) and duration of CPB (p = 0.002). At 1-year post PEA, estimated glomerular filtration rate (eGFR) significantly improved in patients who did not develop AKI [ΔeGFR 5.6 ml/min/1.73 m. Perioperative AKI is associated with higher preoperative circulating ET-1 and it negatively influences long-term kidney function in patients with CTEPH who undergo PEA.

Topics: Acute Kidney Injury; Aged; Biomarkers; Endarterectomy; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Italy; Kidney; Male; Middle Aged; Predictive Value of Tests; Pulmonary Embolism; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Up-Regulation

Contrast-induced acute kidney injury (CI-AKI) is one of the most serious complications in patients who undergo percutaneous coronary intervention (PCI), especially in those with acute coronary syndrome. It has been shown that inflammation may play an important role in the pathophysiology of CI-AKI.. Inflammatory factors may play a predominant role in the prediction of CI-AKI in patients who undergo emergency PCI.. Patients who underwent emergency PCI from 2013 to 2015 were consecutively enrolled and were divided into CI-AKI and non-CI-AKI groups. Logistic analysis was used to identify the risk factors of CI-AKI. Receiver operator characteristic curve analysis was performed to evaluate the area under the curve (AUC) and to establish the optimal cutoff.. A total of 1061 patients were included, and the CI-AKI rate was 5.47% (58/1061). Logistic analysis showed that the white blood cell (WBC) count (odds ratio [OR]: 1.103, 95% confidence interval [CI]: 1.018-1.195, P = 0.016), neutrophil (N) count (OR: 1.134, 95% CI: 1.045-1.232, P = 0.003), neutrophil to lymphocyte ratio (NLR) (OR: 1.105, 95% CI: 1.044-1.169, P = 0.001), C-reactive protein (CRP) level (OR: 1.006, 95% CI: 1.001-1.011, P = 0.020), high-sensitivity C-reactive protein (hs-CRP) level (OR: 1.099, 95% CI: 1.020-1.184, P = 0.013), and big endothelin-1 (ET-1) level (OR: 4.030, 95% CI: 1.989-8.165, P < 0.001) were all significant predictors for CI-AKI, as was the left ventricular ejection fraction and diuretic administration. The AUC of the big ET-1 level was the highest (0.793, 95% CI: 0.733-0.853), followed by the NLR (0.708, 95% CI: 0.641-0.774), hs-CRP level (0.705, 95% CI: 0.627-0.782), CRP level (0.684, 95% CI: 0.607-0.761), N count (0.655, 95% CI: 0.584-0.726), WBC count (0.620, 95% CI: 0.544-0.695), and erythrocyte sedimentation rate (0.611, 95% CI: 0.527-0.695).. The WBC count, N count, NLR, CRP level, hs-CRP level, and big ET-1 level are all associated with an increased risk of CI-AKI, and among which, the big ET-1 level, NLR, and the hs-CRP level might have high predictive value for CI-AKI after an emergency PCI.

Topics: Acute Kidney Injury; Aged; Area Under Curve; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Contrast Media; Emergencies; Endothelin-1; Female; Humans; Inflammation; Inflammation Mediators; Logistic Models; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Multivariate Analysis; Neutrophils; Odds Ratio; Percutaneous Coronary Intervention; Predictive Value of Tests; Radiography, Interventional; Retrospective Studies; Risk Factors; ROC Curve; Treatment Outcome

Uric acid (UA) plays important roles in inducing renal inflammation, intra-renal vasoconstriction and renal damage. Endothelin-1 (ET-1) is a well-known profibrotic factor in the kidney and is associated with fibroblast expansion. We examined the role of hyperuricemia conditions in causing elevation of ET-1 expression and kidney injury.. Hyperuricemia was induced in mice using daily intraperitoneal injection of uric acid 125 mg/Kg body weight. An NaCl injection was used in control mice. Mice were euthanized on days-7 (UA7) and 14 (UA14). We also added allopurinol groups (UAL7 and UAL14) with supplementation of allopurinol 50 mg/Kg body weight orally. Uric acid and creatinine serum were measured from blood serum. Periodic Acid Schiff (PAS) and Sirius Red staining were done for glomerulosclerosis, tubular injury and fibrosis quantification. mRNA expression examination was performed for nephrin, podocin, preproEndothelin-1 (ppET-1), MCP-1 and ICAM-1. PDGFRβ immunostaining was done for quantification of fibroblast, while α-SMA immunostaining was done for localizing myofibroblast. Western blot analysis was conducted to quantify TGF-β1, α-SMA and Endothelin A Receptor (ETAR) protein expression.. Uric acid and creatinine levels were elevated after 7 and 14 days and followed by significant increase of glomerulosclerosis and tubular injury score in the uric acid group (p < 0.05 vs. control). Both UA7 and UA14 groups had higher fibrosis, tubular injury and glomerulosclerosis with significant increase of fibroblast cell number compared with control. RT-PCR revealed down-regulation of nephrin and podocin expression (p < 0.05 vs. control), and up-regulation of MCP-1, ET-1 and ICAM-1 expression (p < 0.05 vs. control). Western blot revealed higher expression of TGF-β1 and α-SMA protein expression. Determination of allopurinol attenuated kidney injury was based on reduction of fibroblast cell number, inflammation mediators and ppET-1 expression with reduction of TGF-β1 and α-SMA protein expression.. UA induced glomerulosclerosis, tubular injury and renal fibrosis with reduction of podocyte function and inflammatory mediator elevation. ET-1 and fibroblast expansion might modulate hyperuricemia induced renal fibrosis.

Topics: Acute Kidney Injury; Animals; Cell Proliferation; Endothelin-1; Fibroblasts; Gene Expression; Hyperuricemia; Inflammation; Mice; Uric Acid

Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed. Serum urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) levels, tissue total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), asymmetric dimethylarginine (ADMA) levels, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity were measured. Tissue mRNA expression levels of peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were analyzed. In addition, renal tissues were evaluated histopathologically and immunohistochemically. All tested drugs reduced renal damage, apoptosis, urea, creatinine, NGAL, TOS, nitric oxide (NO) and ADMA levels, NF-κB, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expressions (P < 0.001). All tested drugs increased SOD activity, GSH-Px activity, TAS levels, TT levels, endothelial nitric oxide synthase (eNOS) expression, dimethylarginine dimethylaminohydrolases (DDAHs) expression, Nrf2 expression and PPAR-ɣ expression (P < 0.001, P < 0.003). These results suggest that CAP, TEL and BM pretreatment could reduce renal IR injury via anti-inflammatory, antioxidant and anti-apoptotic effects.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Animals; Antioxidants; Apoptosis; Arginine; Benzimidazoles; Benzoates; Captopril; Creatine; Endothelin-1; Gene Expression Regulation; Glutathione Peroxidase; Ischemia; Kidney; Lipocalin-2; Lipocalins; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oleanolic Acid; Proto-Oncogene Proteins; Rats; Rats, Wistar; Reperfusion Injury; Sulfhydryl Compounds; Superoxide Dismutase; Telmisartan; Urea

Endothelin-1 (ET-1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ETA receptor contributes to renal injury in a mouse model of sickle cell disease.. Adult, humanized HbSS (homozygous for sickle Hb) mice had increased ET-1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ETA receptor mRNA expression was also elevated in HbSS (sickle) mice although ETB receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ETA receptors in the renal vascular tissue when compared with control mice.. In response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ETA antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ETA receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease.. These data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ETA receptor, and suggest a potential role for ETA receptor antagonism in a treatment strategy.

Topics: Acute Kidney Injury; Anemia, Sickle Cell; Animals; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Female; Gene Knock-In Techniques; Humans; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Reactive Oxygen Species; Receptor, Endothelin A

Renal failure is common in the NICU; Acute Kidney Injury (AKI) occurs in 8-24% of admissions. Although AKI is preventable with early diagnosis, no reliable AKI biomarkers exist. Endothelin-1 (ET-1) has been implicated in renal pathogenesis, and elevated urinary ET-1 (uET-1) levels may correlate with progression of renal dysfunction. The study objectives were to determine whether uET-1 levels correlate with renal function parameters and/or fetal growth restriction, and if uET-1 is a potential neonatal AKI biomarker.. Sixty-three neonates were enrolled and divided into gestational age (GA) groups by weeks: 1) (24-30 6/7; n = 24); 2) (31-36 6/7; n = 26); and 3) (37-42; n = 13). Additional preterm subgroups for fetal growth restriction analysis included: 1) Appropriate for GA (AGA; n = 40), and 2) Small for GA (SGA; n = 10). ET-1 levels, measured using enzyme linked immunosorbent assay, were collected at birth (cord blood) and 24 h ( ± 4) of life (blood/urine).. No correlation was found between uET-1 and blood plasma levels at birth (r = 0.15; p > 0.05) or 24 h (r = 0.17; p > 0.05). uET-1 negatively correlated with GA (r = -0.44; p < 0.001) and GFR (r = -0.34; p < 0.01). uET-1 levels did not correlate with creatinine (r = 0.13; p > 0.05), BUN (r = 0.19; p > 0.05), BUN/Cr ratio (r = 0.15; p > 0.05), or urinary output (r = 0.12; p > 0.05). In fetal growth restriction subgroup analyses: uET-1 levels negatively correlated with GFR in the PT-AGA subgroup (r = -0.38; p = 0.017), but not with PT-SGA (r = 0.01; p > 0.05).. Plasma and uET-1 levels did not correlate; therefore, renal ET-1 excretion may reflect renal ET-1 production. uET-1 levels correlated negatively with GA and GFR. uET-1 may be a marker of impaired neonatal circulatory regulation and consequent renal injury.

Topics: Acute Kidney Injury; Biomarkers; Birth Weight; Creatinine; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Male; Pilot Projects; Predictive Value of Tests; Pregnancy; Prospective Studies; United States

Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) may play important roles in renal fibrosis in the obstructed kidney. However, there have been few clear demonstrations of a relationship between their activation and additive or synergistic roles in renal fibrosis. We investigated the protective roles and relationship between renal RAS and ET-1 in unilateral ureteral obstruction (UUO) mice.. 8-week-old male C57BL/6 mice were divided into seven groups: sham, bosentan+sham, valsartan+sham, vehicle+UUO, bosentan+UUO, valsartan+UUO, and valsartan+bosentan+UUO. Valsartan and bosentan were administered orally using an NG tube (valsartan 10 mg/kg/day, bosentan 100 mg/kg/day for 8 days, after which the molecular and structural kidney parameters were evaluated. Bosentan treatment elevated plasma renin activity, renal renin, and AT1R expression in UUO mice.. Although valsartan decreased plasma ET-1 in these mice, it did not affect ET(A) or ET(B) in their kidneys. Co-treatment with valsartan and bosentan decreased ET-1 in these mice compared to the single treatments. Bosentan, but not valsartan, elevated eNOS expression in their kidneys. Co-treatment with valsartan and bosentan reduced TGF-β, α-SMA, and collagen IV expression, and the Masson's trichrome stained area in their kidneys.. Bosentan and valsartan acted complementarily, and co-treatment with both drugs had an additive protective effect against renal fibrosis.

Topics: Acute Kidney Injury; Animals; Antihypertensive Agents; Bosentan; Drug Synergism; Endothelin-1; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Receptors, Angiotensin; Sulfonamides; Ureteral Obstruction; Valsartan

The present study aims to investigate the possibility that inhibiting the physiological function of endothelin-1 (ET-1) by blocking its receptors would significantly decrease the nephrotoxic effect of cisplatin. Therefore the study was designed to investigate the effect of treatment with BQ-123, the selective endothelin receptor-A (ET(A)) blocker, and bosentan, the non-selective endothelin receptor blocker, on the cisplatin-induced structural, functional, and biochemical alterations in the rat kidney. Rats were divided into four groups: control (given a single dose of normal saline, i.p.), cisplatin (given a single dose of cisplatin, 6mg/kg, i.p.), cisplatin+BQ-123 (1mg/kg, i.p.), and cisplatin+bosentan (30mg/kg, orally via gavage). Each of the two blockers was administered in two doses; 1h before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in blood urea nitrogen and serum creatinine concentrations at 96h following cisplatin injection. Increased concentrations of malondialdehyde, tumor necrosis factor-α (TNF-α) and caspase-3, decreased nitric oxide (NO) production and superoxide dismutase (SOD) activity in kidney homogenates were observed at 96h following cisplatin injection, in addition to a typical 'acute tubular necrosis' pattern. BQ-123 ameliorated the structural and functional injuries caused by cisplatin mainly via restoring SOD activity, in addition to other antioxidant parameters, NO, TNF-α and caspase-3 concentrations. This study further proves that ET(A) but not ETB receptors are involved in cisplatin-induced nephrotoxicity. The selective ET(A) antagonist BQ-123 ameliorated the cisplatin-induced deleterious effects and showed reno-protective effect against cisplatin-induced acute renal damage.

Topics: Acute Kidney Injury; Animals; Caspase 3; Cisplatin; Endothelin A Receptor Antagonists; Endothelin-1; Kidney; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The aim of this study was to assess potential effects of high-tone external muscle stimulation (HTEMS) on parameters of endothelial dysfunction (ED) in patients with acute kidney injury (AKI).. The bad outcome of AKI patients is markedly influenced by ED, microinflammation, oxidative stress and protein hypercatabolism. Recently, we have shown that intradialytic application of HTMS was associated with a faster resolution of AKI. Here, we investigated in the same cohort of patients whether parameters of ED such as nitric oxide (NO), asymmetric-dimethylarginine (ADMA), and endothelin 1 (ET-1) are modulated by HTEMS as compared to non-HTEMS-treated AKI patients.. In a post-hoc study we analyzed plasma samples of the 34 AKI patients stage 5, of whom 17 underwent intradialytic HTEMS treatment while the other 17 served as AKI dialysis controls. Measurements included plasma nitrate and nitrite (NOx), ADMA, ET-1 and were performed before and on days 3, 7, 14, 21, and 28 after start of daily dialysis. Additional 16 healthy volunteers served as controls.. Initially, in both AKI groups NOx levels were markedly lower and ADMA and ET-1 levels were higher compared to the healthy controls. After initiation of daily hemodialysis the HTEMS group showed a faster improvement of NOx and ET-1 (after 1 week) and ADMA levels (after 2 weeks) compared to the No- HTEMS group. After 2 weeks, all parameters of the HTEMS group were not different from healthy controls, while the No-HTEMSAKI group needed 3 - 4 weeks.. Our findings suggest for the first time that in AKI patients, application of HTEMS is associated with a faster normalization of lowered NOx and elevated ADMA and ET-1 plasma levels. We hypothesize that the more rapid amelioration of these parameters in the HTEMS group contributed to the accelerated recovery of AKI. With regard to the small study groups with different causes of AKI, investigations in a greater number of AKI patients is required.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Arginine; Cohort Studies; Electric Stimulation Therapy; Endothelin-1; Female; Humans; Leg; Male; Middle Aged; Muscle, Skeletal; Nitric Oxide; Renal Dialysis

We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)].. Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49).. Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy.. Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified.

Topics: Acute Kidney Injury; Adult; Aged; Antihypertensive Agents; Bosentan; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Receptor, Endothelin A; Scleroderma, Systemic; Sulfonamides; Treatment Outcome

Intracellular Ca(2+) overload is a key factor in contrast-induced renal tubular toxicity. Na(+)/Ca(2+) exchanger (NCX) system is one of main pathways of intracellular Ca(2+) overload. We explore the effects of KB-R7943, an inhibitor of reverse mode of NCX, on contrast-induced acute kidney injury (CI-AKI).. Rats were divided into control, CI-AKI and pre-treatment groups with KB-R7943 (5, 10 mg/kg). CI-AKI was induced by diatrizoate administration in rats with cholesterol-supplemented diet for 8 weeks. Renal function and hemodynamics were determined at Day 1 post-administration. Renal histopathology was observed under light microscope. Renal tubular apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Renal endothelin-1 (ET-1) was measured by radioimmunoassay. The oxidative markers of renal malondialdehyde (MDA) and catalase (CAT) were measured. The expression of NCX was evaluated by reverse transcription-polymerase chain reaction (RT-PCR).. Levels of serum creatinine (Scr, µmol/L ) in CI-AKI rats ((149 ± 35) µmol/L) were significantly higher than those of normal rats ((55 ± 4) µmol/L, P < 0.01). Renal ET-1, MDA and CAT, resistance index (RI) of renal blood vessels increased significantly in CI-AKI rats. The contrast-induced increases in Scr and RI of renal blood vessels were suppressed significantly and dose-dependently by pretreatment with KB-R7943. Histopathological and TUNEL results showed that contrast-induced severe renal tubular necrosis and apoptosis were significantly and dose-dependently attenuated by KB-R7943. KB-R7943 significantly suppressed the contrast-induced increments of ET-1, MDA and CAT. No significant changes in NCX1 mRNA expression were observed following contrast administration.. Renal oxidative stress and ET-1 overproduction via the activation of reverse mode of NCX play an important role in the pathogenesis of CI-AKI. And inhibition of reverse mode of NCX expressed in renal tubular epithelial cell has protective effects on CI-AKI.

Topics: Acute Kidney Injury; Animals; Contrast Media; Endothelin-1; Male; Oxidative Stress; Rats; Rats, Wistar; Sodium-Calcium Exchanger

Impaired nitric oxide (NO) release in chronic renal failure has been implicated in the pathogenesis of hypertension and the progression of renal insufficiency. We investigated whether gene delivery of the endothelial NO synthase (eNOS) improves NO release and reduces blood pressure and renal failure and injury in rats with reduced renal mass.. Renal failure was induced by renal artery branches ligation. Two weeks later, rats with renal failure were divided into three groups and received an intravenous injection of the vehicle or the adenovirus that expresses eNOS or β-galactosidase (β-gal). Systolic blood pressure, renal parameters and histopathology were assessed at Week 4 after gene delivery.. At the end of the study, systolic blood pressures, serum creatinine, proteinuria, urinary endothelin-1 (ET-1) excretion and renal cortex ET-1 levels were increased, whereas plasma and urine NO(2)/NO(3) were reduced in renal failure rats as compared to normal controls. Renal injury comprised blood vessel media hypertrophy, focal and segmental glomerular sclerosis, tubular atrophy and interstitial fibrosis. Gene delivery of eNOS, but not β-gal, prevented an increase in systolic blood pressure and proteinuria, and a reduction in plasma and urine NO(2)/NO(3). eNOS gene delivery also reduced a rise in serum creatinine, urinary ET-1 excretion and renal cortex ET-1 levels, and the renal vascular, glomerular and tubular injury.. This study indicates that eNOS gene delivery in rats with renal failure improves NO release, which likely prevents the aggravation of hypertension and slows down the progression of renal failure and injury.

Topics: Acute Kidney Injury; Adenoviridae; Animals; beta-Galactosidase; Cattle; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Renal Insufficiency

Early urinary biomarkers may be useful in determining the severity of ischemic injury in donation after circulatory death (DCD) kidneys. The aim of this study was to evaluate the efficacy of a collective series of urinary biomarkers in relation to the warm and cold ischemic intervals.. Porcine kidneys were retrieved after 0, 10, and 25 min of warm ischemia (WI), then preserved by static cold storage (CS) for period of 2 and 18 h. After preservation, kidneys were reperfused on an isolated organ perfusion system to assess renal function and injury. Levels of IL-6, TNFα, endothelin-1 (ET-1), and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples after 3 h of reperfusion.. There was no significant difference in renal functional parameters or urinary biomarkers between the WI times when kidneys were stored for 2 h (P > 0.05). After 18 h CS, kidneys with 10 and 25 min of WI demonstrated a significant decline in renal function compared with kidneys without WI (P < 0.05). Levels of ET-1 and NGAL were significantly higher in kidneys with 25 min WI (25 m ET-1, 30.1 ± 21.2, versus 0 m 2.25 ± 1.5 pg/mL; P = 0.002: NGAL, 25 m 77 ± 51 versus 0 m 10 ± 0.1 pg/mL; P = 0.005). Levels of IL-6 and TNFα were significantly higher in kidneys with 10 and 25 min of WI (P = 0.001, 0.001).. Early urinary biomarkers are a useful means to determine graft injury. ET-1 and NGAL are more accurate in predicting the severity of ischemic injury compared with inflammatory markers.

Topics: Acute Kidney Injury; Animals; Biomarkers; Cold Ischemia; Endothelin-1; Interleukin-6; Ischemia; Kidney; Kidney Function Tests; Swine; Tumor Necrosis Factor-alpha; Warm Ischemia

Ischemic acute kidney injury (iAKI) in experimental diabetes mellitus (DM) is associated with a rapid kidney dysfunction more than in non-diabetic rats. We hypothesize that this vulnerability is due to excessive endothelin-1 (ET-1) expression along with dysregulation of nitric oxide synthase (NOS) isoforms. The aim of the present study was to assess the impact of ischemia on renal function in diabetic rats as compared with non-diabetic rats, and to investigate the involvement of ET-1 and NO systems in the susceptibility of diabetic kidney to ischemic damage.. DM was induced by Streptozotocin. iAKI was induced by clamping of left renal artery for 30 min. Right intact kidney served as control. 48 h following ischemia, clearance protocols were applied to assess glomerular filtration rate (GFR), urinary flow (V) and sodium excretion (U(Na)V) in both kidneys. The renal effects of ABT-627, ET(A) antagonist; A192621.1, ET(B) antagonist; L-NAME, NOS non-selective inhibitor; 1400 W, inducible NOS (iNOS) inhibitor; and NPLA, neuronal NOS (nNOS) inhibitor, were assessed following ischemic renal injury in diabetic rats.. Induction of iAKI in diabetic and non-diabetic rats caused significant reductions in GFR, V, and U(Na)V, which were greater in diabetic than non-diabetic rats. While, treatment with ABT-627 decreased V and U(Na)V, and increased GFR, A192621.1 decreased all these parameters. L-NAME, 1400 W, and NPLA improved GFR in the ischemic diabetic kidney.. Excessive vasoconstrictive effects of ET-1 via ET(A) and upregulation of iNOS, are partly responsible for the impaired recovery of renal function following ischemia in diabetic rats.

Topics: Acute Kidney Injury; Animals; Diabetes Mellitus, Experimental; Endothelin-1; Glomerular Filtration Rate; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Reperfusion Injury; Streptozocin; Up-Regulation; Vasoconstriction

The prognosis of patients after acute kidney injury (AKI) is poor and treatment is limited. AKI is mainly caused by renal ischemia/reperfusion injury (IRI). During the extension phase of IRI, endothelial damage may participate in ischemia and inflammation. Endothelin-1 (ET-1) which is mostly secreted by endothelial cells is an important actor of IRI, particularly through its strong vasoconstrictive properties. We aimed to analyze the specific role of ET-1 from the endothelial cells in AKI.. We used mice lacking ET-1 in the vascular endothelial cells (VEETKO). We induced IRI in VEETKO mice and wild type controls by clamping both kidneys for 30min. Sham operated mice were used as controls. Mice were sacrificed one day after IRI in order to investigate the extension phase of IRI. Kidney function was assessed based on serum creatinine concentration. Levels of expression of ET-1, its receptor ET(A), protein kinase C, eNOS, E-Cadherin and inflammation markers were evaluated by real time PCR or western blot. Tubular injury was scored on periodic acid Schiff stained kidney preparations. Lumen and wall area of small intrarenal arteries were measured on kidney slices stained for alpha smooth muscle cell actin. Oxidative stress, macrophage infiltration and cell proliferation was evaluated on slices stained for 8-hydroxy-2'-deoxyguanosine, F4/80 and PCNA, respectively.. IRI induced kidney failure and increased ET-1 and ET(A) receptor expression. This was accompanied by tubular injury, wall thickening and reduction of lumen area/wall area ratio of small renal arteries, increased oxidative stress and inflammation. These parameters were attenuated in VEETKO mice.. Our results suggest that suppression of ET-1 from the endothelial cells attenuates IRI kidney injury. Blocking ET-1 effects may represent a therapeutic strategy in the management of AKI.

Topics: Acute Kidney Injury; Animals; Cadherins; Endothelial Cells; Endothelin-1; Hypoxia; Kidney; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Oxidative Stress; Reactive Oxygen Species; Receptor, Endothelin A; Reperfusion Injury; Vasoconstriction

The molecular mechanism linking aldosterone and endothelin-1 in the development of diabetic nephropathy has not been completely elucidated. Here, we provide evidence showing that streptozotocin-induced diabetic rats have significantly increased aldosterone and endothelin-1 in the kidney tissue and markedly decreased expression of Dot1a and Af9. Blocking aldosterone with spironolactone significantly reduced proteinuria, glomerulosclerosis, tubulointerstitial injury and endothelin-1 expression, and significantly increased Dot1a and Af9 expression. Increasing Dot1a and Af9 expression by spironolactone or by stable transfection led to impaired endothelin-1 expression in NRK-52 cells. In contrast, downregulation of Dot1a and Af9 by aldosterone in NRK-52E cells caused upregulation of endothelin-1. Genetic inactivation of Dot1l, which encodes Dot1a, in Aqp2-expressing principal cells of mouse kidney impaired association of Dot1a and H3 dimethyl K79 with the specific subregions of endothelin-1 promoter, and upregulates endothelin-1 mRNA and protein expression. Our data suggest that Dot1a and Af9 repress endothelin-1 in vitro and in vivo. Excessive aldosterone induces kidney injury, in part possibly by downregulating Dot1a and Af9, and thus relieving Dot1a-Af9-mediated repression to increase endothelin-1 transcription. Spironolactone ameliorates kidney injury in Streptozotocin-induced diabetic rats, possibly by restoring Dot1a-Af9-mediated repression to reduce endothelin-1 expression. Therefore, Dot1a and Af9 as aldosterone-downregulated targets are negative regulators of endothelin-1 transcription in vitro and in vivo, and may be considered as new potential therapeutic targets of kidney injury in diabetes.

Topics: Acute Kidney Injury; Aldosterone; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Down-Regulation; Endothelin-1; Histone-Lysine N-Methyltransferase; Humans; Methyltransferases; Mice; Nuclear Proteins; Promoter Regions, Genetic; Rats; Spironolactone; Streptozocin; Up-Regulation

The objective of the study was to investigate the role of endothelin-1 in the pathogenesis of scleroderma renal crisis in patients with systemic sclerosis. We used immunohistochemical analysis with anti-endothelin-1 and anti-von Willebrand factor antibodies in comparing kidney biopsies from patients with systemic sclerosis and scleroderma renal crisis (n = 14); from normal kidneys (n = 5); and from patients with typical hemolytic uremic syndrome and thrombotic microangiopathy (n = 5), antiphospholipid syndrome (n = 6), diabetic nephropathy (n = 5), minimal change disease with cyclosporine toxicity (n = 5), or nephroangiosclerosis (n = 5). Kidney biopsies from all systemic sclerosis patients presented specific lesions: glomerular lesions with thickened capillary walls (n = 6, 42.8%), mesangiolysis (n = 3, 21.4%), fibrin thrombi (n = 3, 21.4%), hypertrophy of juxtaglomerular apparatus (n = 5, 35.7%), arteriolar lesions showing mucinous intimal thickening and lumen mucoid occlusions (n = 13, 92.8%), proliferation of intimal cells (ie, "onion-skin" lesions; n = 13, 92.8%), fibrinoid necrosis (n = 3, 21.4%), and fibrin thrombosis (n = 4, 28.6%). Chronic lesions in large arteries showed modifications such as fibrous intimal thickening (n = 13, 92.8%). The pattern of endothelial staining for endothelin-1 in both glomeruli and arteriolar lesions appears to be specific for scleroderma renal crisis. Glomerular endothelin-1 staining without arteriolar staining was seen in hemolytic uremic syndrome; and isolated arteriolar staining (without glomerular staining) was seen in a number of conditions including antiphospholipid nephropathy, cyclosporine toxicity, and diabetic nephropathy. Endothelin-1 is overexpressed in glomeruli and arterioles of patients with scleroderma renal crisis, which suggests that endothelin-1 might be a therapeutic target in this condition.

Topics: Acute Kidney Injury; Adult; Aged; Antiphospholipid Syndrome; Endothelin-1; Female; Hemolytic-Uremic Syndrome; Humans; Kidney; Male; Middle Aged; Scleroderma, Systemic; von Willebrand Factor

Acute kidney dysfunction after ischemia-reperfusion injury (IRI) may be a consequence of persistent intrarenal vasoconstriction. Regulators of G-protein signaling (RGSs) are GTPase activators of heterotrimeric G proteins that can regulate vascular tone. RGS4 is expressed in vascular smooth muscle cells in the kidney; however, its protein levels are low in many tissues due to N-end rule-mediated polyubiquitination and proteasomal degradation. Here, we define the role of RGS4 using a mouse model of IRI comparing wild-type (WT) with RGS4-knockout mice. These knockout mice were highly sensitized to the development of renal dysfunction following injury exhibiting reduced renal blood flow as measured by laser-Doppler flowmetry. The kidneys from knockout mice had increased renal vasoconstriction in response to endothelin-1 infusion ex vivo. The intrinsic renal activity of RGS4 was measured following syngeneic kidney transplantation, a model of cold renal IRI. The kidneys transplanted between knockout and WT mice had significantly reduced reperfusion blood flow and increased renal cell death. WT mice administered MG-132 (a proteasomal inhibitor of the N-end rule pathway) resulted in increased renal RGS4 protein and in an inhibition of renal dysfunction after IRI in WT but not in knockout mice. Thus, RGS4 antagonizes the development of renal dysfunction in response to IRI.

Topics: Acute Kidney Injury; Animals; Cysteine Proteinase Inhibitors; Disease Models, Animal; Endothelin-1; Enzyme Activation; GTP-Binding Protein alpha Subunits, Gq-G11; Kidney; Kidney Transplantation; Laser-Doppler Flowmetry; Leupeptins; Ligation; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nephrectomy; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Renal Circulation; Reperfusion Injury; RGS Proteins; Time Factors; Vasoconstriction; Vasoconstrictor Agents

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA2 mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23+/-3%; p<0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60+/-20%; p<0.05) but reduced AngII vasoconstriction (51+/-11%; p<0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB2 levels in ARF. Candoxatril reduced plasma AngII by 34+/-4% (p<0.05) in ARF which was approximately 3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na+ and creatinine excretion in ARF by 73+/-9% and 33+/-2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Administration, Oral; Angiotensin II; Animals; Antihypertensive Agents; Creatinine; Endothelin-1; Indans; Kidney; Male; Natriuresis; Neprilysin; Nitrates; Propionates; Proteinuria; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Systemic Sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs and extensive vasculopathy. We report a case of a 41 year-old white woman with a 10 year-history of limited scleroderma, who developed the rare combination of Scleroderma Renal Crisis (SRC) and Systemic Sclerosis related Pulmonary Arterial Hypertension (SScPAH) in the same time. Although the patient received the proposed antihypertensive treatment, the renal function did not recover, and she initiated on renal replacement therapy. SRC and SScPAH are two aspects of SSc vasculopathy characterized by endothelial dysfunction mediated by endothelin-1 and other vasoactive hormones. Further new studies with therapies directed towards the underlying mechanisms of SRC (i.e. endothelin-receptor antagonists), which are proven helpful in SScPAH, should take place to establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium is currently poor.

Topics: Acute Kidney Injury; Adult; Endothelin-1; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Renal Replacement Therapy; Scleroderma, Systemic

Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50-80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI. Studies were conducted in a normotensive endotoxemia-induced AKI model in mice by intraperitoneal injection of 3.5 mg/kg LPS. Serum ghrelin levels were increased during endotoxemia accompanied by increased ghrelin receptor (GHSR-1a) protein expression in the kidney. Ghrelin administration (1.0 mg/kg sc 6 h and 30 min before and 14 h after LPS) significantly decreased serum cytokine levels (TNF-alpha, IL-1beta, and IL-6) and serum endothelin-1 levels which had been induced by LPS. The elevated serum nitric oxide (NO) levels and renal inducible NO synthase expression were also decreased by ghrelin. Renal TNF-alpha levels were also increased significantly in response to LPS and ghrelin significantly attenuated this increase. When administrated before LPS, ghrelin protected against the fall in glomerular filtration rate at 16 h (172.9 +/- 14.7 vs. 90.6 +/- 15.2 microl/min, P < 0.001) and 24 h (147.2 +/- 20.3 vs. 59.4 +/- 20.7 microl/min, P < 0.05) as well as renal blood flow at 16 h (1.65 +/- 0.07 vs. 1.47 +/- 0.04 ml/min, P < 0.01) and 24 h (1.56 +/- 0.08 vs. 1.22 +/- 0.03 ml/min, P < 0.05) after LPS administration without affecting mean arterial pressure. Ghrelin remained renal protective even when it was given after LPS. In summary, ghrelin offered significant protection against endotoxemia-induced AKI. The renal protective effect of ghrelin was associated with an inhibition of the proinflammatory cytokines. Of particular importance was the suppression of TNF-alpha both in the circulation and kidney tissues. Thus, ghrelin may be a promising peptide in managing endotoxemia-induced AKI.

Topics: Acute Kidney Injury; Animals; Body Weight; Cyclic GMP; Endothelin-1; Endotoxemia; Escherichia coli Infections; Ghrelin; HMGB1 Protein; Kidney; Kidney Function Tests; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Receptors, Ghrelin; Tumor Necrosis Factor-alpha

The aim was to investigate the role of endothelin 1 receptor subtypes in the early renal response to lipopolysaccharide (LPS) during normotensive endotoxemia with acute kidney dysfunction. Endotoxemia was induced in thiobutabarbital-anesthetized rats (n = 9 per group) by infusion of LPS (dosage, 1 mg/kg per hour i.v.). The study groups (1) sham-saline, (2) LPS-saline, (3) LPS-BQ123, (4) LPS-BQ788 and (5) LPS-BQ123 + BQ788 received isotonic saline, the ETA receptor antagonist BQ-123 (dosage, 30 nmol/kg per minute i.v.), and/or the ETB receptor antagonist BQ-788 (dosage, 30 nmol/kg per minute i.v.) before and during 2 h of LPS infusion. Renal clearance measurements, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark-type microelectrodes) were analyzed throughout. Before LPS administration, there were no significant differences between groups in glomerular filtration rate (GFR), RBF, or in cortical (CLDF) and outer medullary perfusion. However, mean arterial pressure (MAP) was elevated in LPS-BQ788 group compared with LPS-BQ123 + BQ788 group (P < 0.05). In saline-treated rats, endotoxin induced an approximate 35% reduction in GFR (P < 0.05), without significant effects on MAP, RBF, or on CLDF and cortical PO2. In addition, LPS increased outer medullary perfusion and PO2 (P < 0.05). The fractional urinary excretion rates of sodium, potassium, and water were not significantly different in LPS-saline group compared with sham-saline group. Neither selective nor combined ETA and ETB receptor blockade improved GFR. In BQ-788-infused rats, endotoxin produced marked reductions in RBF (-18% +/- 4% [P < 0.05]) and CLDF (-18% +/- 2% [P < 0.05]). Similarly, endotoxin decreased RBF (-14% +/- 3% [P < 0.05]) and CLDF (-10% +/- 2% [P < 0.05]) in LPS-BQ123 + BQ788 group. Endotoxin reduced MAP (-22% +/- 4% [P < 0.05]) in BQ-123-treated rats but did not significantly influence MAP in other groups. We conclude that in early normotensive endotoxemia, ETB receptors exert a renal vasodilator influence and contribute to maintain normal RBF.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Disease Models, Animal; Endothelin B Receptor Antagonists; Endothelin-1; Endotoxins; Glomerular Filtration Rate; Lipopolysaccharides; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Renal Circulation; Vasodilation

Ischemia/reperfusion (I/R) injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure. Previous studies have shown that ozone oxidative preconditioning (OzoneOP) attenuated renal I/R injury. The objective of this study was to examine the hypothesis that protective effects of OzoneOP in renal I/R injury were associated with endogenous NO.. In a right-nephrectomized rat mode, anesthetized rats underwent 45 min of renal ischemia. OzoneOP (1 mg/kg) was administered before I/R injury. Rats were killed at 24, 48, and 72 h after I/R injury and blood samples and renal tissues were obtained.. OzoneOP prevented the renal dysfunction induced by I/R and increased nitric oxide (NO) release and renal NO synthase (endothelial, eNOS, and inducible, iNOS) expression. In contrast, enhancement of endothelin-1 in the kidney after the reperfusion was markedly suppressed by OzoneOP.. Our findings indicated that the protective effect of OzoneOP was closely related to the NO production following the increase in eNOS and iNOS expression. Ozone treatment may have important clinical implications, particularly in view of the minimizing renal damage before transplantation.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Endothelin-1; Glutathione; Glutathione Peroxidase; Guanidines; Ischemic Preconditioning; Kidney; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ozone; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

We evaluated the effects of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a Na+/H+ exchanger (NHE) inhibitor, on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in mice. Ischemic ARF was induced by clamping the left renal artery and vein for 40 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Preischemic treatment with EIPA attenuated the I/R-induced renal dysfunction. Histopathological examination of the kidney of ARF mice revealed severe renal damage such as tubular necrosis and proteinaceous casts in the tubuli. Histologically evident damage was also improved by preischemic treatment with EIPA. In addition, the I/R-induced increase in renal endothelin-1 (ET-1) content was suppressed by preischemic treatment with EIPA, reflecting the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. However, the postischemic treatment with EIPA failed to improve the I/R-induced renal dysfunction and ET-1 overproduction. These findings suggest that NHE activation, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of I/R-induced renal injury. The inhibition of NHE by EIPA may be considered as a therapeutic approach to protect the postischemic ARF.

Topics: Acute Kidney Injury; Amiloride; Animals; Endothelin-1; Kidney; Kidney Tubular Necrosis, Acute; Kidney Tubules; Male; Mice; Protective Agents; Reperfusion Injury; Sodium-Hydrogen Exchangers

To examine whether a novel endothelin receptor antagonist, CPU0213, is effective in relieving the acute renal failure (ARF) of septic shock by suppressing the activated endothelin-reactive oxygen species (ET-ROS) pathway and nuclear factor kappa B (NF-kappaB).. The cecum was ligated and punctured in rats under anesthesia. CPU0213 (30 mg .kg(-1).d(-1), bid, sc X 3 d) was administered 8 h after surgical operation.. In the untreated septic shock group, the mean arterial pressure and survival rate were markedly decreased (P<0.01), and heart rate, weight index of kidney, serum creatinine and blood urea nitrogen, 24 h urinary protein and creatinine were significantly increased (P<0.01). The levels of ET-1, total NO synthetase (tNOS), indusible nitric oxide synthetase (iNOS), nitric oxide (NO), and ROS in serum and the renal cortex were markedly increased (P<0.01). The upregulation of the mRNA levels of preproET-1, endothelin converting enzyme, ET(A), ET(B), iNOS, and tumor necrosis factor-alpha in the renal cortex was significant (P<0.01). The protein amount of activated NF-kappaB was significantly increased (P<0.01) in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration.. Upregulation of the ET signaling pathway and NF-kappaB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ET(A) and ET(B) receptors in the renal cortex following CPU0213 medication.

Topics: Acute Kidney Injury; Animals; Endothelin Receptor Antagonists; Endothelin-1; Kidney Cortex; Male; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pyrazoles; Rats; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Shock, Septic; Tumor Necrosis Factor-alpha

The effects of tempol, a superoxide dismutase mimetic, on ischemia/reperfusion-induced acute renal failure (ARF), noradrenaline (NA) overflow and endothelin-1 (ET-1) overproduction in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine concentration, and fractional excretion of sodium, NA concentrations in renal venous plasma, and renal ET-1 contents were determined. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Pre-ischemic treatment with tempol (10, 100 mg/kg, i.v.) dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, which were also significantly suppressed by the tempol treatment. There was a significant increase in NA concentrations in renal venous plasma after the ischemia/reperfusion, and this increase was markedly suppressed by the treatment with tempol. In addition, tempol treatment significantly attenuated the increment of ET-1 content in the kidney exposed to the ischemia/reperfusion. These findings suggest that tempol improves the post-ischemic renal injury by inhibiting the neural activity of renal sympathetic nerve and ET-1 overproduction.

Topics: Acute Kidney Injury; Animals; Cyclic N-Oxides; Endothelin-1; Gene Expression; Kidney; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spin Labels

Acute renal failure (ARF) occurs in some adult patients with minimal change nephropathy (MCN). To investigate clinical and pathological factors associated with developing ARF, we compared clinical features and kidney pathological characteristics of endothelin 1 (ET-1) expression in patients with adult-onset MCN with and without ARF.. The patient population consisted of 53 patients consecutively diagnosed with adult-onset MCN during a 10-year period. Based on creatinine clearance, 25 patients were assigned to the ARF group and 28 patients were assigned to the non-ARF group.. Clinical data show that the ARF group had a higher blood pressure, higher serum cholesterol level, and lower serum albumin level than the non-ARF group. Pathological data showed more severe foot-process effacement, interstitial edema, and flattened tubular epithelium in the same group. Greater ET-1 expression was detected in vessels, tubules, and glomeruli of the ARF compared with non-ARF group. The ARF group experienced a lower steroid response rate. However, there was no significant difference in stability of remission to steroid treatment in patients who achieved a remission.. ARF associated with enhanced kidney ET-1 expression is a reversible complication of MCN that occurs frequently in patients with apparently expanded extracellular fluid. Presumptively, ARF may develop as an amplification of the underlying pathogenesis of MCN involved in enhanced ET-1 expression, which may be superimposed by a transient episode of circulatory insufficiency during diuretic treatment.

Topics: Acute Kidney Injury; Adult; Age of Onset; Aged; Blood Pressure; Cholesterol; Cyclophosphamide; Diuretics; Edema; Endothelin-1; Epithelial Cells; Extracellular Fluid; Female; Humans; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Remission Induction; Renal Circulation; Serum Albumin; Vasoconstriction

To study endothelial function in different variants of acute renal failure (ARF) at various stages of the disease.. The study of 36 patients with severe ARF at the stages of oliguria and recovery of diuresis included a clinico-laboratory analysis of characteristics of ARF of various etiology and follow-up of plasmic concentrations of endothelin-1, thromboxan A2 and prostacyclin in different ARF variants at different ARF stages.. The oliguric phase of severe ARF ran with significant elevation of the level of vasoconstrictive endothelial hormones (endothelin-1 and thromboxan A2 and a fall of a vasodilator prostacyclin. Recovery of diuresis normalized the above parameters.. Mechanisms of ARF development involve endothelial dysfunction manifesting with alteration of vasoactive hormones synthesis with a dominant rise of a vasoconstrictive hormones concentration.

Topics: Acute Kidney Injury; Adult; Down-Regulation; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2; Up-Regulation

The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF.. Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF.. Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only approximately 35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure.. These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF.

Topics: Acute Kidney Injury; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Infusions, Intravenous; Kidney; Losartan; Male; Models, Animal; Rats; Rats, Wistar; Reperfusion Injury; Sulfonamides

Ischemic acute renal failure (ARF) is a common and often fatal condition characterized by tubular epithelial cell necrosis and marked monocyte infiltration. Inflammatory mechanisms, including cell adhesion, cell infiltration, and cytokine production, are involved. These processes are thought to be directly or indirectly regulated by nuclear factor kappaB (NF-kappaB). Targeted of NF-kappaB might ameliorate ischemia/reperfusion (I/R) injury by inhibiting the production of genes that involved in ischemic ARF. The objective of the present study was to evaluate the effect of NF-kappaB decoy oligodeoxynucleotides (ODN) in experimental rat ischemic ARF.. Ischemic ARF was induced by left renal artery clamping for 60 minutes, while the right kidney was being removed in female Sprague-Dawley rats. The effect of cationic liposome-protamine-NF-kappaB decoy ODN was evaluated after infusion into the kidney via the renal artery before clamping. After 24 hours of reperfusion, we then assessed morphologic and functional parameters, NF-kappaB/DNA binding activity, monocyte/macrophage (M/MPhi) infiltration, and gene expression in I/R kidney.. After 24 hours of reperfusion, compared with sham-operated animals, serum creatinine and blood urea nitrogen (BUN) levels in ischemic ARF animals were increased about 10-fold and fivefold respectively. (255.67 +/- 34.48 micromol/L vs. 25.33 +/- 2.23 micromol/L and 43.47 +/- 5.50 mmol/L vs. 8.45 +/- 0.43 mmol/L, P < 0.001), NF-kappaB/DNA binding activity was markedly elevated [median value was 1.75 vs. 0.15 relative density unit (RDU), P < 0.005]. NF-kappaB decoy ODN treatment reduced the elevation of serum creatinine level by 70% (79.17 +/- 8.64 micromol/L vs. 255.67 +/- 34.48 micromol/L, P < 0.01), BUN level by 40% (28.33 +/- 4.86 mmol/L vs. 43.47 +/- 5.50 mmol/L, P= NS), and almost abolished the NF-kappaB activation compared with levels observed in sham-operated rats (median value was 0.25 vs. 1.9 RDU, P < 0.005). Furthermore, NF-kappaB decoy ODN pretreatment prevented the occurrence of tubular necrosis and reduced the renal tubular damage scores markedly (1.85 +/- 0.06 vs. 3.63 +/- 0.06 scores, P < 0.01). In addition, M/MPhi infiltration was obviously suppressed (9.77 +/- 1.19 cells/hpf vs. 29.22 +/- 1.94 cells/hpf, P < 0.01), Moreover, results of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry showed the up-regulation of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) was greatly decreased, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expression were also reduced, approaching levels observed in sham-operated animals. The data suggest that NF-kappaB decoy ODN treatment protects renal tissue from the effects of I/R injury and thus reduces the severity of ARF.. These experiments demonstrated that NF-kappaB plays a critical role in renal I/R injury by reducing a series of inflammatory genes. NF-kappaB decoy ODN treatment reduces the renal dysfunction and damage associated with ischemic ARF. Therefore, in vivo transfection of NF-kappaB decoy ODN provides a new therapeutic strategy for ischemic ARF.

Topics: Acute Kidney Injury; Animals; Cations; Chemokine CCL2; Endothelin-1; Female; Genetic Therapy; Intercellular Adhesion Molecule-1; Lipids; Macrophages; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oligodeoxyribonucleotides; Protamines; Rats; Rats, Sprague-Dawley; Renal Artery; Reperfusion Injury; Transfection

To elucidate the role of nitric oxide in the pathogenesis of ischemic acute renal failure, we investigated the effects of FK409, a spontaneous nitric oxide donor, and N(G)-nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction in post-ischemic kidneys. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 hours after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage of the kidney. Increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2 and 24 hours after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, intravenously) dose-dependently ameliorated renal injuries and suppressed the elevation of endothelin-1 content induced by ischemia/reperfusion. In contrast, N(G)-nitro-L-arginine methyl ester (1 or 10 mg/kg, intravenously) pretreatment dose-dependently aggravated renal injuries of acute renal failure rats, and the effect is accompanied by further increase in the renal endothelin-1 contents. These results suggest that both exogenous and endogenous nitric oxide have protective effects against ischemia/reperfusion-induced renal dysfunction and tissue damage, probably through the suppression of endothelin-1 overproduction in post-ischemic kidneys.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Injections, Intravenous; Kidney; Kidney Function Tests; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitro Compounds; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

It is known that 17beta-estradiol (E2-beta) increases the production of nitric oxide. We have demonstrated that E2-beta prevents renal injury and suppresses renal endothelin-1 overproduction in ischemic acute renal failure in rats. In the present study, we investigated whether N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, can reverse the effect of E2-beta in ischemic acute renal failure. Ischemic acute renal failure was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. Pre-ischemic treatment with E2-beta (100 microg/kg, intravenously) attenuated the ischemia/ reperfusion-induced renal dysfunction and suppressed the increment of renal endothelin-1 content 24 hours after reperfusion. The effects of E2-beta on renal dysfunction and increased endothelin-1 content in acute renal failure rats were reversed by pretreatment with N(G)-nitro-L-arginine methyl ester (0.3 mg/kg, intravenously). An in vivo microdialysis study revealed that the concentration of nitric oxide metabolites in the kidney was reduced during ischemia, and quickly recovered after reperfusion in E2-beta-treated acute renal failure rats, compared with cases in untreated acute renal failure rats. This recovery of renal nitric oxide metabolite concentration with E2-beta was abolished by the pretreatment with N(G)-nitro-Larginine methyl ester. These findings suggest that nitric oxide is closely related to suppressive effect of E2-beta on renal endothelin-1 overproduction in acute renal failure rats and this suppression is probably involved in the beneficial effect of E2-beta on ischemia/reperfusion-induced renal injury.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Estradiol; Kidney; Kidney Function Tests; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

To determine the roles of endothelin (ET) and nitrogen monoxide (NO) in the adenine-induced acute renal failure (ARF) models.. ARF models were established by feeding adenine in rats. The activity of NO synthase (NOS) in kidneys of rats was tested by NADPH-diaphorase. Expression of endothelin-1 (ET-1) in kidneys of rats was studied by immunoreactivity method. The area densities for ET-1 and NOS expressions in kidneys were determined by CMM3 pathology image analysis system to calculate the mean light density.. Expressions of ET-1 in normal rat kidneys were wide and weak, but they were greatly enhanced in medulla renis of the ARF models while remained unchanged in the cortex. The activities of NOS were stronger in the cortex and the inner medulla than in the outer medulla. The renal functions of the ARF models were improved after they were treated with L-argine, but the expressions of ET-1 and NOS were not improved. After the withdrawal of adenine, the ARF model rats recovered gradually in their renal functions, and the same was true for the expressions of ET-1 and NOS.. ET-1 and NO both play important roles in the occurrence, development and recovery of ARF. It is supposed that L-Arg can partly protect the renal functions of ARF rats.

Topics: Acute Kidney Injury; Adenine; Animals; Endothelin-1; Male; Nitric Oxide; Nitric Oxide Synthase; Random Allocation; Rats; Rats, Wistar

Possible involvement of nitric oxide (NO) in the protective effect of ischemic preconditioning against the ischemia/reperfusion-induced acute renal failure was investigated. Ischemic preconditioning, which consists of three cycles of 2-minute ischemia followed by 5-minute reperfusion, was performed prior to 45-minute ischemia. Ischemic preconditioning significantly improved the renal dysfunction induced by 45-minute ischemia followed by 24-hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45-minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning, and these increases correlated with changes in endothelial NO synthase (eNOS) protein expression in renal tissues. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG-nitro-L-arginine, a nonselective NOS inhibitor, but not with aminoguanidine, an inducible NOS inhibitor. In addition, increment of endothelin-1 (ET-1) content in the kidney after the reperfusion was markedly suppressed by ischemic preconditioning treatment. These findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion -induced acute renal failure is closely related to the renal nitric oxide production following the increase in eNOS expression after the reperfusion and that the suppressive effect of ischemic preconditioning on the ischemia/reperfusion -induced renal ET-1 overproduction may be partly involved in the ameliorating effect of ischemic preconditioning.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Endothelin-1; Enzyme Inhibitors; Guanidines; Ischemic Preconditioning; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley

About 30% of cadaveric renal allografts, but almost never living-donor kidneys, develop postischemic acute renal-transplant failure (ARF). We therefore quantified the expression of essential reperfusion regulators in different compartments of cadaveric and living-donor kidney biopsies.. Specimens were obtained from donor kidneys at the end of the cold ischemia time before implantation and categorized into three groups according to donor source and early posttransplant function. Ten living-donor biopsies (LIV) were compared with nine cadaveric kidney biopsies (CAD) with primary posttransplant function (CAD-PF) and to nine with ARF (CAD-ARF). Laser capture microdissection was used to isolate glomeruli from tubulointerstitium. The gene expression of intercellular adhesion molecule (ICAM)-1, interleukin (IL)-1beta, endothelin (ET)-1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) was quantified in glomeruli and tubulointerstitium by real-time polymerase chain reaction (TaqMan).. Tubulointerstitial areas of all CAD kidneys revealed significantly lower mRNA levels of all investigated genes compared with LIV. Tubulointerstitial ET-1, iNOS, and eNOS in CAD-ARF averaged only half of the expression in CAD-PF kidneys. ICAM-1 and IL-1beta mRNA concentrations were equal in CAD-PF and CAD-ARF. Glomerular expression of the investigated genes was equal in CAD and LIV kidneys with the exception of ICAM-1 and ET-1, which were two times higher in CAD-PF compared with LIV and CAD-ARF.. These data suggest that CAD compared with LIV kidneys have an impaired expression of immune and vasoregulatory genes in the tubulointerstitium, which may represent reduced cellular vitality and capacity to adaptation. The observed further reduction of ET-1, iNOS, and eNOS expression in CAD-ARF might contribute to reperfusion injury and delayed allograft function.

Topics: Acute Kidney Injury; Adult; Biopsy; Endothelin-1; Gene Expression; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Ischemia; Kidney; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; RNA, Messenger; Tissue Donors; Transplantation, Homologous

Topics: Acute Kidney Injury; Endothelin-1; Gene Expression; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Ischemia; Kidney; Kidney Glomerulus; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Tissue Donors

Using Na(+)/Ca(2+) exchanger (NCX1)-deficient mice, the pathophysiological role of Ca(2+) overload via the reverse mode of the Na(+)/Ca(2+) exchanger in ischaemia/reperfusion-induced renal injury was investigated. Since NCX1(-/-) homozygous mice die of heart failure before birth, we utilized NCX1(+/-) heterozygous mice. The ischaemia/reperfusion-induced renal dysfunction in heterozygous mice were significantly attenuated compared with cases in wild-type mice. Also, histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca(2+) deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. The increase in renal endothelin-1 (ET-1) content was significantly greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. We conclude that Ca(2+) overload via the reverse-mode of Na(+)/Ca(2+) exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of ischaemia/reperfusion-induced acute renal failure.

Topics: Acute Kidney Injury; Animals; Calcium; Endothelin-1; Immunohistochemistry; Kidney; Male; Mice; Mice, Knockout; Reperfusion Injury; Sodium-Calcium Exchanger

We investigated whether the treatment with 17 beta-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17 beta-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24 h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17 beta-oestradiol (20 or 100 microg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17 beta-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17 beta-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

Topics: Acute Kidney Injury; Animals; Endothelin-1; Estradiol; Kidney; Male; Models, Animal; Rats; Rats, Sprague-Dawley

This study evaluated the role of endothelin B (ET ) receptor-mediated action in the development and maintenance of ischemic acute renal failure (ARF), using the spotting-lethal ( ) rat that carries a naturally occurring deletion in the ET receptor gene. Because homozygous ( ) rats die shortly after birth due to congenital distal intestinal aganglionosis, genetic rescue of rats from the developmental defect using a dopamine-beta-hydroxylase (DbetaH)-ET transgene was performed to produce ET -deficient adult rats. Rescued homozygous (DbetaH-ET ) and wild-type (DbetaH-ET +/+) rats were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histologic damage, such as proteinaceous casts in tubuli, were markedly and observed equally in homozygous and wild-type groups, and these renal injuries gradually recovered. However, when the ischemia/reperfusion-induced renal injury was examined 7 days after the reperfusion, the recovery in homozygous ARF rats was obviously delayed compared with the wild-type animals. Two of the eight homozygous ARF rats died within 3 days after the reperfusion. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ET receptor-mediated actions do not play an important role in the development of ischemic ARF but may be involved in the recovery process from ischemia/reperfusion-induced renal injury.

Topics: Acute Kidney Injury; Animals; Animals, Genetically Modified; Endothelin-1; Ischemia; Kidney; Rats; Receptor, Endothelin B; Receptors, Endothelin

1. In the present study, we investigated whether treatment with alpha-lipoic acid (LA), a powerful and universal anti-oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF). 2. Ischaemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Blood urea nitrogen (BUN), plasma concentrations of creatinine (Pcr) and urinary osmolality (Uosm) were measured for the assessment of renal dysfunction. Creatinine clearance (Ccr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. 3. Renal function in ARF rats decreased markedly 24 h after reperfusion. Intraperitoneal injection of LA at a dose of 10 mg/kg before the occlusion tended to attenuate the deterioration of renal function. A higher dose of LA (100 mg/kg) significantly (P < 0.01) attenuated the ischaemia/reperfusion-induced increases in BUN (19.1 +/- 0.7 vs 7.2 +/- 0.7 mmol/L before and after treatment, respectively), Pcr (290 +/- 36 vs 78.1 +/- 4.2 micromol/L before and after treatment, respectively) and FENa (1.39 +/- 0.3 vs 0.33 +/- 0.09% before and after treatment, respectively). Treatment with 100 mg/kg LA significantly (P < 0.01) increased Ccr (0.70 +/- 0.13 vs 2.98 +/- 0.27 mL/min per kg before and after treatment, respectively) and Uosm (474 +/- 39 vs 1096 +/- 80 mOsmol/kg before and after treatment, respectively). 4. Histopathological examination of the kidney of ARF rats revealed severe lesions. Tubular necrosis (P < 0.01), proteinaceous casts in tubuli (P < 0.01) and medullary congestion (P < 0.05) were significantly suppressed by the higher dose of LA. 5. A marked increase in endothelin (ET)-1 content in the kidney after ischaemia/reperfusion was evident in ARF rats (0.43 +/- 0.02 ng/g tissue) compared with findings in sham- operated rats (0.20 +/- 0.01 ng/g tissue). Significant attenuation (P < 0.01) of this increase occurred in ARF rats treated with the higher dose of LA (0.24 +/- 0.03 ng/g tissue). 6. These results suggest that administration of LA to rats prior to development of ischaemic ARF prevents renal dysfunction and tissue injury, possibly through the suppression of overproduction of ET-1 in the postischaemic kidney.

Topics: Acute Kidney Injury; Animals; Antioxidants; Blood Urea Nitrogen; Creatinine; Endothelin-1; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thioctic Acid

We investigated the effects of pre- or post-ischemic treatment with KB-R7943, a new Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure (ARF) in rats, and these were compared with the effects of verapamil. Ischemic ARF was induced by clamping the left renal pedicle for 45-min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function markedly decreased 24 h after reperfusion. Pre-ischemic treatment with KB-R7943 or verapamil attenuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was overcome by post-ischemic treatment with KB-R7943 but not with verapamil. Histopathological examination of the kidney of ARF rats revealed severe renal damage, and suppression of the damage was seen with post-ischemic treatment with KB-R7943. KB-R7943 markedly suppressed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. No significant changes in Na+/Ca2+ exchanger protein expression in renal tissue were observed with 45-min ischemia, 6 h after reperfusion and KB-R7943 treatment. These results suggest that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by ET-1 overproduction, seems to play an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943, which is effective in both cases of pre- and post-ischemic treatments, may prove to be an effective therapeutic agent for cases of ischemic ARF.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Blood Urea Nitrogen; Blotting, Western; Calcium Channel Blockers; Endothelin-1; Heart Rate; Hemodynamics; Homeodomain Proteins; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea; Verapamil

We investigated whether the preischemic or postischemic treatment with KB-R7943, a novel and selective Na+/Ca2+ exchange inhibitor, has renal protective effects in mice with ischemic acute renal failure (ARF). Ischemic ARF was induced by clamping the left renal pedicle for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was markedly diminished 24 h after reperfusion. Preischemic treatment with KB-R7943 attenuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was also overcome by postischemic treatment with KB-R7943. Histopathologic examination of the kidneys of ARF mice revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Histologically evident damage and Ca2+ deposition in necrotic tubular epithelium were improved by preischemic treatment with KB-R7943. In addition, preischemic treatment with KB-R7943 significantly suppressed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. These findings suggest that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943 may prove to be an effective therapeutic agent for cases of ischemic ARF in humans.

Topics: Acute Kidney Injury; Animals; Calcium; Endothelin-1; Ischemia; Kidney; Male; Mice; Reperfusion Injury; Sodium-Calcium Exchanger; Thiourea

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Creatinine; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Heterozygote; Homozygote; Hypertension, Renovascular; Immunohistochemistry; Kidney; Membrane Proteins; Mice; Mice, Knockout; Nephrectomy; Organ Size; Receptor, Endothelin A; Renal Artery Obstruction; RNA, Messenger; Severity of Illness Index; Survival Rate

To elucidate the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF), we examined the effect of a selective proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfusion. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg before the occlusion tended to attenuate the deterioration of renal function. The higher dose of lactacystin (1 mg/kg) markedly attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, endothelin (ET)-1 content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after the reperfusion, and this elevation was abolished by the higher dose of lactacystin. These results indicate that lactacystin prevents the development of ischemia/reperfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ischemic ARF, possibly through the enhancement of ET-1 production in postischemic kidneys.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Endothelin-1; Ischemia; Kidney; Male; Multienzyme Complexes; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury

Previous studies showed that unilateral renal damage is attenuated by prior contralateral uninephrectomy (Nx) in ischaemia-induced acute renal failure (ARF). Since renal ischaemia increases endothelin-1 (ET-1) production in the kidney, we examined whether the alteration of renal ET-1 content may contribute to the nephrectomy-induced attenuation of renal injury.. Ischaemic renal injury was provoked by 60-min left renal artery occlusion (RAO). Removal of the right kidney was performed just before RAO in the Nx group. Forty-eight hours after release of the clamp, renal ET-1 content was measured in both non-nephrectomized and unilaterally nephrectomized rats. We also examined the effects of a selective ET(A) receptor (FR139317) and monoclonal ET antibody (AwETN40) on the RAO-induced changes in renal haemodynamics at 2 and 48 h after RAO respectively.. The plasma concentration of ET-1 did not change in the two groups of ARF rats, but the cortical content of ET-1 increased to a lesser extent in Nx animals after ischaemia. Prior removal of the right kidney significantly facilitated the percentage recovery of left renal blood flow (RBF) during the first 2 h after release of the clamp. The percentage recovery of inulin clearance (Cin) by the kidney was also significantly better in Nx than sham-Nx rats at 48 h after RAO. Continuous administration of FR139317 (50 mg/kg/day) using osmotic minipumps for 3 days significantly attenuated exogenous ET-1-induced decrease in Cin and RBF. Infusion of FR139317 restored the decrease in RBF to control values during first 2 h in sham-Nx rats. However, FR139317 and AwETN40 did not ameliorate the RAO-induced decline of Cin in sham-Nx or Nx rats at 2 and 48 h after ischaemia respectively.. Contralateral uninephrectomy prior to ischaemia-induced ARF attenuated the increase in cortical ET-1 content and subsequent renal response to ischaemic injury. This beneficial effect of unilateral nephrectomy, however, was not mediated through well-preserved RBF due to reduced intrarenal ET-1 action.

Topics: Acute Kidney Injury; Animals; Antibodies, Monoclonal; Azepines; Endothelin-1; Endothelins; Hemodynamics; Indoles; Inulin; Ischemia; Kidney; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury

Parathyroid hormone (PTH)-related protein (PTHrP) is present in many normal tissues, including the kidney. Current evidence supports that PTHrP is involved in renal pathophysiology, although its role on the mechanisms of renal damage and/or repair is unclear. Our present study examined the changes in PTHrP and the PTH/PTHrP receptor (type 1) in folic acid-induced acute renal failure in rats. The possible role of PTHrP on the process of renal regeneration following folic acid administration, and potential interaction between angiotensin II (Ang II) and endothelin-1, and PTHrP, were examined in this animal model.. PTHrP, PTH/PTHrP receptor, ACE, and preproendothelin-1 (preproET-1) mRNA levels in the rat kidney were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and/or RNase protection assay. Immunohistochemistry also was performed for PTHrP, the PTH/PTHrP receptor, and Ang II in the renal tissue of folic acid-injected rats. The role of PTHrP on tubular cell proliferation following folic acid injury was investigated in vitro in rat renal epithelial cells (NRK 52E). PTHrP secretion in the medium conditioned by these cells was measured by an immunoradiometric assay specific for the 1-36 sequence.. Using RT-PCR, PTHrP mRNA was rapidly (1 hour) and maximally increased (3-fold) in the rat kidney after folic acid, decreasing after six hours. At 72 hours, renal function was maximally decreased in these rats, associated with an increased PTHrP immunostaining in both renal tubules and glomeruli. In contrast, the PTH/PTHrP receptor mRNA (RNase protection assay) decreased shortly after folic acid administration. Moreover, PTH/PTHrP receptor immunostaining dramatically decreased in renal tubular cell membranes after folic acid. A single subcutaneous administration of PTHrP (1-36), 3 or 50 microg/kg body weight, shortly after folic acid injection increased the number of tubular cells staining for proliferating cell nuclear antigen by 30% (P < 0.05) or 50% (P < 0.01), respectively, in these rats at 24 hours, without significant changes in either renal function or calcemia. On the other hand, this peptide failed to modify the increase (2-fold over control) in ACE mRNA, associated with a prominent Ang II staining into tubular cell nuclei, in the kidney of folic acid-treated rats at this time period. The addition of 10 mmol/L folic acid to NRK 52E cells caused a twofold increase in PTHrP mRNA at six hours, without significant changes in the PTH/PTHrP receptor mRNA. The presence of two anti-PTHrP antibodies, with or without folic acid, in the cell-conditioned medium decreased (40%, P < 0.01) cell growth.. Renal PTHrP was rapidly and transiently increased in rats with folic acid-induced acute renal failure, featuring as an early response gene. In addition, changes in ACE and Ang II expression were also found in these animals. PTHrP induces a mitogenic response in folic acid-damaged renal tubular cells both in vivo and in vitro. Our results support the notion that PTHrP up-regulation participates in the regenerative process in this model of acute renal failure and is a common event associated with the mechanisms of renal injury and repair.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Cell Division; Disease Models, Animal; Endothelin-1; Endothelins; Epithelial Cells; Folic Acid; Immunohistochemistry; Kidney Cortex; Kidney Tubules; Male; Parathyroid Hormone-Related Protein; Peptidyl-Dipeptidase A; Protein Precursors; Proteins; Rats; Rats, Wistar; Regeneration; Up-Regulation

Angiotensin II and endothelin-1, major endogenous vasoconstrictors in acute renal failure (ARF), can modulate the effects of each other. This study aimed to evaluate the interaction between these vasoconstrictors in glycerol-induced ARF by evaluating their effects in the isolated perfused kidney in the presence of their respective antagonists. In ARF, angiotensin II (2.5-25 ng) caused an increase in perfusion pressure. Saralasin, 1 microM, a nonselective angiotensin receptor antagonist, reduced these responses by 61+/- 6% (p < 0.05). Surprisingly, SQ29548, 1 microM, a selective PGH2 /thromboxane A2 receptor blocker, also reduced angiotensin II responses (62 +/- 4%; p < 0.05). BQ610 1 microM, an ETA -selective receptor antagonist, was without effect, but BQ788 1 microM, an ETB -selective antagonist, attenuated the response by 70 +/- 4% (p < 0.05). In ARF, in contrast to angiotensin II, vasoconstriction by endothelin-1 (5-25 ng) was diminished. Saralasin further attenuated endothelin-1 response by 65 +/- 2% (p < 0.05), whereas SQ29548 was without effect. BQ788 reduced the responses by 67 +/- 7% (p < 0.05), whereas BQ610 was without effect (42 +/- 30%; p > 0.05). BQ610 and BQ788 combination further reduced vasoconstriction by 89 +/- 3% (p < 0.05). Responses to U46619 were not changed in ARF. However, saralasin and BQ788, but not BQ610, attenuated its vasoconstrictor action. We conclude that vascular responses in ARF may be attributed to enhanced responses to angiotensin II through activation of ETB and/or PGH2 /thromboxane A2 receptors. We also suggest that the vasoconstrictor response to endothelin-1 in ARF is predominantly ETB receptor-mediated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Angiotensin II; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Glycerol; In Vitro Techniques; Male; Perfusion; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents

We investigated the effects of ABT-627, a selective ETA-receptor antagonist, and A-192621, a selective ETB-receptor antagonist, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min, 2 weeks after the contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion and thereafter tended to recover gradually. ABT-627 (1 mg/kg, i.v.) administration before ischemia markedly attenuated the renal dysfunction induced by the ischemia/reperfusion, whereas A-192621 (3 mg/kg, i.v.) pretreatment was without effect. Histopathological examination of the kidney of untreated ARF rats revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion. Histologically evident damage was improved by pretreatment with ABT-627, but not with A-192621. Daily oral administration of ABT-627 (10 mg/kg per day), but not A-192621 (30 mg/kg per day), given after the ischemia/reperfusion period also exerted protective effects. These findings clearly indicate that endothelin, acting via the ETA receptor, participates in the pathogenesis of ischemic ARF. Thus, selective ETA-receptor antagonism may be useful in the treatment of human ischemic ARF, whereas selective blockade of the ETB receptor will probably be ineffective.

Topics: Acute Kidney Injury; Animals; Atrasentan; Endothelin Receptor Antagonists; Endothelin-1; Ischemia; Kidney; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reperfusion Injury

Effects of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl- 1-1-phenyl- 1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt), a novel endothelin converting enzyme (ECE) inhibitor, on ischemic acute renal failure (ARF) in rats were examined in comparison with those of phosphoramidon, a conventional ECE inhibitor. ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Intravenous bolus injection of SM-19712 (3, 10, 30 mg/kg) prior to the occlusion attenuated dose-dependently the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were dose-dependently attenuated by SM-19712. Protective effects of phosphoramidon (10 mg/kg) on ARF-induced functional and tissue damages were less potent than that of the same dose of SM-19712. Endothelin-1 (ET-1) content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after reperfusion, and this elevation was completely suppressed by the higher dose of SM-19712. Our findings support the view that renal ET-1 plays an important role in the development of ischemia/reperfusion-induced renal injury. SM-19712 may be useful in the treatment of ischemic ARF.

Topics: Acute Kidney Injury; Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Ischemia; Kidney Function Tests; Male; Metalloendopeptidases; Protective Agents; Rats; Rats, Sprague-Dawley; Sulfonamides; Sulfonylurea Compounds

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 +/- 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 +/- 1.1 ng/l; n = 10), normals (1.2 +/- 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 +/- 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 +/- 0.6 vs. 0.89 +/- 0.05 mg/dl, P < 0.05), creatinine clearance (107 +/- 9 ml/min vs. 44.6 +/- 5.5 ml/ min, P < 0.001), and bilirubin (11.4 +/- 3.8 vs. 3.7 +/- 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS.

Topics: Acute Kidney Injury; Analysis of Variance; Bilirubin; Biomarkers; Creatinine; Endothelin-1; Hepatorenal Syndrome; Humans; Kidney Failure, Chronic; Liver Failure; Liver Transplantation; Postoperative Complications; Reference Values; Time Factors

The objectives of this study were (1) to assess the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF) induced by ischemia-reperfusion, and (2) to determine the involvement of this proteolytic pathway in the enhanced production of renal endothelin-1 (ET-1) in this model of ARF. ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured to test the effectiveness of drugs used. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evident in the ARF rats, compared to the sham-operated rats. Intraperitoneal injection of a proteasome inhibitor (PSI), N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, at a dose of 1 mg/kg, 1 h before the clamping, significantly attenuated the renal function impairment in the ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. On the other hand, a calpain inhibitor, calpeptin, had little effect at the same dose. These results suggest that a proteasome-dependent proteolytic pathway is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.

Topics: Acute Kidney Injury; Animals; Cysteine Endopeptidases; Endothelin-1; Ischemia; Kidney; Male; Multienzyme Complexes; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley

Acute renal failure and veno-occlusive disease of the liver are serious complications following stem cell transplantation (SCT) and contribute to the non-relapse mortality associated with this procedure. Endothelins, a family of vasoconstrictor peptides, may be involved in the pathogenesis of a variety of renal and hepatic diseases, including CsA-associated hypertension and the hepatorenal syndrome. In order to study the relevance of endothelins to SCT-related liver and kidney dysfunction, we determined endothelin-1 (ET-1) levels in plasma samples obtained from 65 patients (38 autologous, 27 allogeneic) 7 days before and 7, 14 and 28 days after SCT. A steady increase in plasma ET-1 was observed after SCT (5.36 pg/ml, 95% CI 4.30-6.43 on day +28 vs 3.82 pg/ml, 95% CI 3.21-4.43 on day -7; P = 0.020). No differences in ET-1 levels existed between autologous and allogeneic SCT recipients at any of the time points studied (P = 0.561). In addition, no significant differences were observed among patients with renal dysfunction vs those without (P = 0.187), nor in patient groups with or without hepatic dysfunction (P = 0.075). In conclusion, even though plasma ET-1 levels showed a steady increase following SCT, no correlation could be found with development of SCT-related kidney or liver dysfunction.

Topics: Acute Kidney Injury; Adolescent; Adult; Cyclosporine; Endothelin-1; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Male; Middle Aged

During endotoxemia, there is a marked and intractable decrease in systemic blood pressure, as well as profound vasoconstriction of the renal artery, thereby leading to septic shock and acute renal failure. The purpose of this study was to elucidate the effect of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, on the hemodynamic and renal vascular changes seen in endotoxemia.. Prospective, comparative, experimental study.. Laboratory at a university hospital.. Thirty-two male mongrel dogs (12.1+/-0.4 kg) under pentobarbital anesthesia.. Four groups of animals were studied: a) the lipopolysaccharide (LPS) group (n = 10), which received LPS (250 ng/kg/min for 2 hrs); b) the TAK-044 (a nonselective endothelinA/ endothelinB receptor antagonist) plus LPS group (n = 12), which received a bolus of TAK-044 (5 mg/kg) 0.5 hr before the start of LPS infusion; c) the TAK-044 plus vehicle group (n = 5), which received the same dose of TAK-044 0.5 hr before the start of vehicle infusion; and d) the control group (n = 5), which received only vehicle infusion.. Changes in systemic and renal hemodynamics, blood gas, and renal function were measured at baseline, and at 0.5, 1, 2, 3, and 4 hrs. Infusion of LPS resulted in significant decreases in mean arterial pressure, arterial pH, Pao2, base excess, urine volume, renal blood flow, creatinine clearance, and urine osmolality. The administration of TAK-044 before LPS infusion did not affect the LPS-induced hypotension. In contrast, the receptor antagonist prevented LPS-induced metabolic acidosis and hypoxemia, and improved LPS-induced decreases in urine volume, renal blood flow, creatinine clearance, and urine osmolality, whereas TAK-044 or vehicle administered alone resulted in no significant hemodynamic or blood gas changes. Plasma endothelin-1 concentrations significantly increased after LPS infusion, with or without TAK-044.. The present study suggests that endothelin-1 plays an important role in the impaired renal hemodynamics and renal function associated with endotoxemia, and that endothelin receptor antagonists may be useful as therapeutic agents for acute renal failure during endotoxemia.

Topics: Acute Kidney Injury; Animals; Blood Gas Analysis; Critical Care; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Hemodynamics; Lipopolysaccharides; Male; Peptides, Cyclic; Prospective Studies; Renal Circulation

Endothelin (ET), a potent vasoconstrictor, is known to play a role in ischemic acute renal failure. Although preproET-1 (ppET-1) mRNA is known to be up-regulated following ischemia/reperfusion injury, it has not been determined which component of the injury (ischemia or reperfusion) leads to initial gene up-regulation. Likewise, although ET-1 peptide expression has been localized in the normal kidney, its expression pattern in the ischemic kidney has not been determined. Therefore, the purpose of this study was twofold: (a) to determine whether ischemia alone or ischemia plus reperfusion is required for the up-regulation of ppET-1 mRNA to occur, and (b) to localize ET-1 peptide expression following ischemia in the rat kidney to clarify better the role of ET in the pathophysiology of ischemia-induced acute renal failure.. Male Lewis rats underwent clamping of the right renal vascular pedicle for either 30 minutes of ischemia (group 1), 60 minutes of ischemia (group 2), 30 minutes of ischemia followed by 30 minutes of reperfusion (group 3), or 60 minutes of ischemia followed by three hours of reperfusion (group 4). The contralateral kidney acted as a control. ppET-1 mRNA up-regulation and ET-1 peptide expression were examined using the reverse transcription-polymerase chain reaction and immunohistochemistry, respectively.. Reverse transcription-polymerase chain reaction yielded a control (nonischemic) value of 0.6 +/- 0.2 densitometric units (DU) of ppET-1 mRNA in the kidney. Group 1 levels (30 min of ischemia alone) were 1.8 +/- 0.4 DU, a threefold increase (P < 0.05). Group 2 levels (60 min of ischemia alone) increased almost six times above baseline, 3.5 +/- 0.2 DU (P < 0.01), whereas both group 3 and group 4 (ischemia plus reperfusion) did not experience any further significant increases in mRNA levels (1.9 +/- 0.4 DU and 2.8 +/- 0.6 DU, respectively) beyond levels in group 1 or 2 animals subjected to similar ischemic periods. ET-1 peptide expression in the ischemic kidneys was significantly increased over controls and was clearly localized to the endothelium of the peritubular capillary network of the kidney.. Initial ET-1 gene up-regulation in the kidney occurs secondary to ischemia, but reperfusion most likely contributes to sustaining this up-regulation. The marked increase of ET-1 in the peritubular capillary network suggests that ET-induced vasoconstriction may have a pathophysiological role in ischemic acute tubular necrosis.

Topics: Acute Kidney Injury; Animals; Base Sequence; Capillaries; DNA Primers; Endothelin-1; Endothelins; Endothelium, Vascular; Immunohistochemistry; Kidney; Kidney Tubular Necrosis, Acute; Male; Protein Precursors; Rats; Rats, Inbred Lew; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.

Topics: Acute Kidney Injury; Animals; Aorta; Endothelin-1; Endothelins; Endothelium, Vascular; In Vitro Techniques; Male; Protein Precursors; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Renal Artery; RNA, Messenger; Vasoconstriction; Vasoconstrictor Agents

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors; pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ET(B) receptors; pA(2) = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concentrations in conscious rats in a dose-dependent fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has acute hemodynamic effects and decreases blood pressure. Tezosentan is also able to prevent the acute renal failure that complicates rhabdomyolysis in a rat model of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent elimination half-life of less than 1 h in rabbits and primates and of 2 h in rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions.

Topics: Acute Kidney Injury; Animals; Aorta, Thoracic; Cell Adhesion; Cell Membrane; Cells, Cultured; CHO Cells; Cricetinae; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; In Vitro Techniques; Macaca fascicularis; Macaca mulatta; Male; Microsomes; Pyridines; Rabbits; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Spodoptera; Tetrazoles; Trachea

Scleroderma renal crisis (SRC) developed in two patients with systemic sclerosis (SSc) and they died from respiratory failure. Findings on autopsy revealed congestion and oedema in both lungs and intimal thickening of the small renal arteries in both patients. Immunohistological investigations showed positive staining of anti-human endothelin (ET)-1 in the media of the small renal arteries and ET-B receptor in the medial smooth muscle of the small renal arteries. This observation suggests an important pathophysiological role of ET-1 in the development of SRC in some patients with SSc.

Topics: Acute Kidney Injury; Aged; Endothelin-1; Fatal Outcome; Female; Humans; Immunohistochemistry; Kidney; Middle Aged; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Renal Artery; Scleroderma, Systemic

Gentamicin-induced acute renal failure is characterized by a decrease in renal plasma flow and creatinine clearance. Endothelins (ET) are potent renal vasoconstrictors. The aim of this work is to assess the role of ET-1 in gentamicin-induced renal failure. Renal glomerular release of ET-1 was measured in rats with gentamicin-induced nephrotoxicity (100 mg/kg/day, s.c. for 2, 4 or 6 days). Glomeruli were isolated and incubated for 24 h in RPMI-1640. Glomerular supernatant and plasma concentration of ET-1 were measured by RIA. Renal failure was assessed by insulin, para-aminohippuric and creatinine clearance and histological studies. Gentamicin induced a dose number-dependent increase in plasma creatinine and a decrease in creatinine clearance. This was accompanied by a marked decrease in inulin and para-aminohippuric acid clearance, as well as by a marked tubular necrosis, without alterations in glomerular structures. Plasma ET-1 concentration and glomerular ET-1 release were also increased in gentamicin-treated rats. When 10-5 M gentamicin was added to control glomeruli, ET-1 production was not modified (36.4 +/- 2.2 vs. 35.2 +/- 1.7 pg/ml/24 h). All these results suggest that elevated ET-1 plasma levels and increased glomerular release of ET-1 could mediate, at least in part, the decrease in glomerular filtration rate observed in gentamicin-induced ARF.

Topics: Acute Kidney Injury; Animals; Creatinine; Culture Techniques; Endothelin-1; Female; Gentamicins; Kidney; Kidney Glomerulus; Microscopy, Electron; Rats; Rats, Wistar

Topics: Acute Kidney Injury; Animals; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Kidney; Rats

To understand the changes of urinary endothelin-1 (ET-1) concentrations in acute renal failure (ARF) and to investigate the origin of human urinary ET-1, we studied urinary ET-1 excretion in 70 normal children and 12 children with ARF caused by tubular dysfunction. Urinary ET-1 excretion was expressed as a ratio of urinary ET-1 to urinary creatinine (ET-1/Cr). Among healthy children, the highest urinary ET-1/Cr values were found during infancy. In patients with ARF, there was a positive correlation between urinary ET-1/Cr values and daily total urinary ET-1 (r = 0.42, n = 26, p < 0.05). Plasma ET-1 concentrations were elevated in children with ARF during the period of peak serum creatinine concentration. During the course of ARF, the lowest urinary ET-1/Cr value occurred during the period of peak serum creatinine, whereas the plasma ET-1 concentration declined after the peak. These results provide insight into the developmental changes of urinary ET-1 values in normal children, and illustrate the pattern of changes in plasma and urinary ET-1 concentrations during the course of ARF in children. The results suggest that renal production, rather than clearance from the circulation by glomerular filtration, may be the source of urinary ET-1.

Topics: Acute Kidney Injury; Adolescent; Child; Child, Preschool; Endothelin-1; Humans; Kidney Tubules

A progressive fall in glomerular capillary plasma flow (QA) is observed in mercury chloride (HgCl2)-induced acute renal failure (ARF) although the site of the main lesion of this ARF is the proximal tubule. To elucidate this mechanism, we examined the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) protein at the glomerulus level in the kidneys of control rats and rats with HgCl2-induced ARF. Both ET-1 and eNOS protein were detected in the juxtaglomerular cells of afferent arterioles. The expression of ET-1 was significantly increased in ARF rats when compared to control rats. Inversely, the expression of eNOS protein was markedly reduced in ARF rats as opposed to control rats. These observations suggest the participation of the vasoconstrictor, ET-1 and the vasodilator, NO in a reduction in QA observed in HgCl2-induced ARF.

Topics: Acute Kidney Injury; Animals; DNA Primers; Endothelin-1; Female; Immunoenzyme Techniques; Juxtaglomerular Apparatus; Kidney Cortex; Mercuric Chloride; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; RNA, Messenger

This experiment was designed to help understand the cascade of events that end in renal impairment in septic animals.. Twenty 3- to 8-day-old piglets were anesthetized and the femoral artery, jugular and femoral veins, and bladder were catheterized. After stabilization under anesthesia with ventilatory support, they were divided into a control group and three groups that received endotoxin (ETX) in doses of 0.01 mg/kg, 0.025 mg/kg, and 0.05 mg/kg. Blood pressure and blood gases were monitored continuously. Blood and urine samples were obtained before (B), 1 hour (E1), and 3 hours (E3) after the bolus of ETX to determine glomerular filtration rate (GFR), fractional excretion of sodium (FENa), tumor necrosis factor (TNF), and endothelin-1 (ET-1) levels.. Incremental doses of ETX induce greater release of ET-1 with an early proportionate increase in FENa (P< .05) and late decrease in GFR (P< .05). TNF release is dose and time dependent after ETX injection (P < .05).. ET-1 and FENa are the best tests to evaluate renal failure during early sepsis in neonatal piglets.

Topics: Acute Kidney Injury; Animals; Animals, Newborn; Endothelin-1; Multiple Organ Failure; Sepsis; Sodium; Swine; Tumor Necrosis Factor-alpha

To elucidate the mechanisms underlying the development of HgCl2-induced acute renal failure (ARF), we examined the expression of endothelin (ET)-1, endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS, and a role of angiotensin II (ANG II) and tumor necrosis factor (TNF) in glomeruli and cortices from rats at 20 h after exposure of HgCl2. Prepro-ET-1 and iNOS mRNA were significantly increased in glomeruli and cortices from rats with HgCl2-induced ARF. However, eNOS mRNA was markedly decreased in glomeruli of rats with HgCl2-induced ARF. Blockade of the action of endogenous ANG II with TCV-116, an ANG II receptor type 1 antagonist, or prior administration of TNF antibody (Ab) neutralizing TNF bioactivity or aminoguanidine, an iNOS inhibitor, substantially suppressed the increase in the expression of prepro-ET-1 or iNOS mRNA seen in rats with HgCl2-induced ARF. Both TCV-116 and TNF Ab had no effects on the expression of eNOS mRNA. The abundance of ET-1, iNOS, and eNOS proteins was paralleled by the magnitude of each mRNA expression. Additionally, the aggravation of blood urea nitrogen and serum Cr observed in rats with HgCl2-induced ARF were significantly ameliorated together with the alleviation of proximal tubule epithelial cell injury when the expression of prepro-ET-1 or iNOS mRNA was blunted by prior administration of TCV-116 or prior injection of TNF Ab or aminoguanidine. These observations indicate that ANG II, ET-1, and NO may play an important role in the progression of HgCl2-induced ARF through the acceleration of proximal tubule epithelial cell injury and the deterioration of glomerular hemodynamics. In HgCl2-induced ARF, the gene expression of ET-1 or iNOS is at least in part up-regulated at the transcription level by endogenous ANG II or TNF.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Urea Nitrogen; Chromium; Creatinine; Disease Progression; Endothelin-1; Female; Immunohistochemistry; Kidney Tubules; Mercuric Chloride; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Tumor Necrosis Factor-alpha

To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients.. Observational study.. University teaching hospital intensive care unit.. 12 critically ill patients with acute renal failure receiving their first episode of CVVH.. Blood samples were collected prior to starting CVVH and at 15 min and 1, 3-4, 8-12, and 24 h, and at 24-h intervals thereafter until the filter clotted.. Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients.. The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation Factors; Critical Illness; E-Selectin; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hemofiltration; Humans; Intensive Care Units; Male; Middle Aged; Respiratory Distress Syndrome; Treatment Outcome

The role of endothelin in the normal kidney function, as well as in disease states, has been studied in animal models. In addition, it was shown previously that endothelial, mesangial, and epithelial components of the nephron produce endothelins, in particular ET-1. We performed immunohistochemistry for ET-1 reactivity on 31 autopsy and four surgically removed kidneys. Eighteen cases had clinical diagnoses of acute renal failure (ARF) In the remaining 17 cases with normal or unchanged renal function before death or surgery, ET-1 immunoreactivity was present in tubular epithelium, with the most intense staining in the medullary collecting tubules. In 13 of 18 cases of ARF, tubular staining was either replaced or accompanied by interstitial reactivity in the inner and outer medulla, corresponding to the location of the vasa recta and interlobular arteries identified by factor VIII immunostaining. Controlled autolysis performed on normal kidney over 72 hours postmortem produced tubular epithelial degradation with reduced epithelial cell endothelin reactivity, but not an interstitial pattern. In situ hybridization for ET mRNA localized expression to tubular and collecting duct epithelium in both normal and acute renal failure cases. The change in the localization of ET-1 immunoreactivity from tubular epithelium to the interstitium in these ARF cases does not appear to be the result of increased vascular endothelial production of endothelin. This altered immunoreactivity pattern for ET-1 may be a marker of antemortem tubular damage and can be used as an adjunct in the autopsy diagnosis of ARF.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Autolysis; Biomarkers; Child, Preschool; Endothelin-1; Endothelium, Vascular; Female; Humans; Immunohistochemistry; In Situ Hybridization; Kidney Tubules; Male; Middle Aged; RNA, Messenger

Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.

Topics: Acetamides; Acute Kidney Injury; Animals; Aorta; Constriction; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Hemodynamics; Ischemia; Kidney; Male; Postoperative Complications; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Renal Circulation; Vascular Resistance

The authors study mechanisms of nephrotoxic action of high-osmolar radiopaque substance (RPS) and the role of endothelin-1, hormonal endothelial factor, in these mechanisms in patients with different variants of chronic glomerulonephritis. Endothelin-1 is a potent endogenic vasoconstrictor participating in regulation of intrarenal hemodynamics and renal function the synthesis of which id related to Ca metabolism. Mechanisms of nephrotoxic action of RPS involve disturbances of Ca metabolism (hypercalcemia), high concentration of blood endothelin-1 which directly correlated with baseline creatinine in the serum and deterioration of renal function after RPS introduction. Ca ions antagonists (corinfar) contribute to prevention of changes in endothelin-1 synthesis relevant renal dysfunction induced by RPS.

Topics: Acute Kidney Injury; Adolescent; Adult; Calcium; Calcium Channel Blockers; Contrast Media; Creatinine; Diatrizoate Meglumine; Endothelin-1; Female; Humans; Hypercalcemia; Kidney; Male; Middle Aged; Nifedipine; Time Factors

In this study, the involvement of osteopontin in a rat model of ischemia-induced acute renal failure (ARF) was evaluated. In unilaterally nephrectomized Sprague Dawley rats where the left artery was occluded for 30 min., plasma creatinine levels increased significantly within two hours following reperfusion indicating the onset of renal failure. Northern analysis of kidney cortical RNA from these rats showed a time-dependent increase in osteopontin mRNA expression that was significantly higher than sham-operated rats. Since endothelin-1 (ET-1) is implicated as a mediator of acute renal failure, we evaluated its effects on osteopontin expression in a rat mesangial cell-line. Data from in vitro studies indicated that endothelin-1 (ET-1) caused a modest but reproducible increase in osteopontin mRNA in these cells. While the signal for osteopontin upregulation in the rat model is not known, ET-1, which is known to be increased during ischemia, may contribute at least in part to this process.

Topics: Acute Kidney Injury; Animals; Cell Line; Cytokines; Endothelin-1; Glomerular Mesangium; Ischemia; Kidney; Kidney Cortex; Male; Nephrectomy; Osteopontin; Rats; Rats, Sprague-Dawley; Renal Artery; RNA, Messenger; Sialoglycoproteins; Transcription, Genetic

In order to investigate endothelial cell dysfunction in patients with impaired renal function, we measured circulating endothelin (ET-1) and thrombomodulin (Tm) concentrations used as markers for endothelial cell injury in patients with renal failure. 1) ET-1 and Tm were significantly higher in patients with renal failure and pre-dialysis patients than in normal subjects. Tm in CRF patients was significantly greater than that in ARF patients. In contrast, ET-1 was significantly greater in ARF than in CRF. 2) A positive correlation was found between serum creatinine concentration (Cr) and Tm in pre-dialysis patients. However, no correlation was found between Cr and ET-1. 3) A positive correlation was found between Tm and the duration of dialysis in HD patients, but not in CAPD patients. 4) With the improvement of renal function after regular HD treatment, a substantial reduction was found in ARF patients in both Tm and ET-1, but not in CRF patients. The present study suggests the presence of endothelial cell dysfunction in patients with impaired renal function. The progression of endothelial cell damage may differ between patients on HD and those on CAPD. In addition, it is suggested that endothelial cell dysfunction reverses in ARF patients with improved renal function.

Topics: Acute Kidney Injury; Creatinine; Endothelin-1; Endothelium; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Insufficiency; Thrombomodulin

To study the pathological significance of circulating endothelin (ET) in ARF, we measured plasma ET in seven children (mean age 8.8 +/- 4.4 years) with ARF in the most severe phase and 3.7 +/- 3.5 months later in the recovery period. Twenty-seven healthy children were included in the study as controls. Plasma ET level was measured by highly sensitive and specific radioimmunoassay for ET-1 and ET-2 (ET-1/2, Biomedica, Vienna). Plasma ET was significantly higher in the most severe phase of ARF (4.75 +/- 4.08 fM/ml) than in the recovery period (0.78 +/- 0.24 fM/ml; p < 0.01), but comparing to plasma ET in the healthy children, the difference was only of borderline statistical significance (Pf, 0.0573). Since plasma concentrations of creatinine did not correlate with plasma ET in patients, either in acute or in the recovery phase of disease, we concluded that decreased GFR is not the main factor determining an increased ET in ARF. We suggest that elevated plasma ET in ARF may be secondary to vascular endothelial dysfunction and speculate that enhancement synthesis of endothelial relaxing factor (EDRF) inhibits ET synthesis during the recovery period. We did not find any relationship between plasma ET and blood pressure (BP) in patients with ARF, so we conclude that circulating ET is not the main factor determining BP in ARF.

Topics: Acute Kidney Injury; Biomarkers; Blood Pressure; Child; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Radioimmunoassay