endothelin-1 and Nephritis--Interstitial

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

to characterize the markers of endothelial dysfunction and the effect of antihypertensive drugs on them in patients with chronic urate tubulointestinal nephritis (UTIN) and articular gout.. The study enrolled 81 patients aged 39 to 59 years with gout and urate nephropathy. All the patients were diagnosed as having grade 1-2 arterial hypertension. A lower glomerular filtration rate (GFR) was noted in 49.9%; microalbuminuria (MAU) and elevated serum endothelin-1 (ET-1) levels were recorded in all the patients. Combination antihypertensive therapy based on the use of angiotensin-converting enzyme (ACE) inhibitors and/or an angiotensin II receptor blocker (ARB) in combination with calcium channel blockers was performed during 12 months. The time course of changes in blood pressure, the parameters of target organ lesion, and the markers of endothelial dysfunction were monitored.. Before the study, all the examinees were found to have MAU and increased serum ET-1, which are regarded simultaneously as signs of renal lesion and as markers of endothelial function. A combination of an ACE inhibitor or an ARB could diminish albuminuria and reduce ET-1 concentrations, lower systolic and diastolic blood pressure significantly, and increase GFR.. The patients with articular gout and chronic UTIN are observed to have signs of endothelial dysfunction eliminated by combination antihypertensive therapy.

Topics: Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Calcium Channel Blockers; Drug Therapy, Combination; Endothelin-1; Endothelium, Vascular; Female; Gout; Humans; Hypertension; Male; Middle Aged; Nephritis, Interstitial; Serum Albumin; Treatment Outcome; Uric Acid

To investigate the therapeutic mechanisms underlying prostaglandin E1 (PGE1) and angiotensin-converting enzyme inhibitor (ACEI) on reducing urinary protein in diabetic kidney disease (DKD). DKD rats were established and randomly divided into four groups: PGE1 (10 μg/kg/day) (P group), ACEI (10 mg/kg/day) (A group), combination of PGE1 with ACEI treatment (P + A group), and saline treatment group (DKD group). Untreated rats were used as normal control (N group). Urinary albumin, endothelin-1 (ET-1), angiotensin II (AngII), TUNEL assay, Masson's trichrome staining, and immunohistochemistry staining for CD68 were evaluated in all groups. Ten days after treatment, urinary albumin was significantly decreased in the P and P + A groups (p < 0.01 vs. the DKD group). At the end of 8 weeks, the albumin was still significantly reduced in the P + A group (p < 0.05 vs. the A group). ET-1 and AngII were also significantly decreased in three treatment groups (p < 0.01 vs. the DKD group), especially in the P + A group. Few cells underwent apoptosis in glomerular regions in DKD rats, while amounts of apoptotic cells were seen in tubules regions. Further, apoptosis and the areas of fibrosis in tubulointerstitial were both decreased most in the P + A group compared with the DKD group. Apoptosis of renal tubular epithelial cells may participate in the development and progression of DKD in rats. Combination of PGE1 with AGEI remarkably protects renal function compared with PGE1 or ACEI monotherapy. The potential therapeutic mechanisms of PGE1 and AGEI might be via multiple targets and, at least in part, through inhibiting the apoptosis of renal tubular epithelial cells.

Topics: Alprostadil; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Endothelin-1; Epithelial Cells; Kidney Tubules; Macrophages; Male; Nephritis, Interstitial; Rats, Wistar

To identify the risk factors of kidney injuries in hypertensive patients with uric acid (UA) metabolic disorders in order to choose the optimal management tactics, by analyzing the changes in markers for endothelial dysfunction (endothelin-1 (ET-1), microalbuminuria (MAU), intima-media thickness (IMT)) and tubulointerstitial tissue lesion (beta2-microglobulin (beta2-MG, monocyte chemotactic protein-1 (MCP-1)).. Eighty-one patients with grade 1 hypertension without associated diseases, diabetes mellitus, or metabolic syndrome were examined. There were 3 study groups: 1) hyperuricosuria (n = 7); 2) hyperuricemia (n = 53); 3) hyperuricemia and renal failure (n = 6); and a control group of 15 hypertensive patients without UA metabolic disorders who were matched for age and gender with the patients of the study groups.. The hypertensive patients with hyperuricemia, as compared with those without UA metabolic disorders, showed higher plasma concentrations of ET-1 (p = 0.003) and MAU (p = 0.009) and more marked increases in common carotid IMT (p = 0.044), urinary excretion of beta2-MG (p = 0.010), and MCP-1 (p = 0.030). There were direct correlations between all the examined biomarkers and the degree of uricemia (Rs = 0.453; p < 0.001; Rs = 0.411; p < 0.001; Rs = 0.322; p = 0.067; Rs = 0.537; p < 0.001; and Rs = 0.318; p = 0.004, respectively) and between the markers of endothelial dysfunction and those of tubulointerstitial tissue lesion (Rs = 0.295 for ET-1 and MCP-1; p = 0.008; Rs = 0.399 for ET-1 and beta2-MG; p < 0.001; Rs = 0.462 for MAU and beta2-MG; p < 0.001; and Rs = 0.188 for MAU and MCP-1; p = 0.094). Multivariate analysis of the clinical and laboratory parameters under study confirmed the role of serum MCP-1, beta2-MG, MAU, creatinine levels as independent predictors for decreased relative urinary gravity, the clinical sign of tubulointerstitial tissue lesion/fibrosis, and that of a wider range of the indicators, such as MAU, ventricular septal thickness, glomerular filtration rate, relative urinary gravity, systolic blood pressure, MPC-1, low-density lipoproteins, as risk factors for renal filtrating dysfunction.

Topics: Albuminuria; beta 2-Microglobulin; Biomarkers; Chemokine CCL2; Comorbidity; Endothelin-1; Endothelium; Female; Humans; Hypertension; Hyperuricemia; Male; Metabolic Diseases; Middle Aged; Nephritis, Interstitial; Renal Insufficiency; Risk Factors; Uric Acid

The objective of this study was to detect the expression of Angiotensin-II (Ang-II), Hypoxia-inducible factor-1α (HIF-1α) and Endothelin-1 (ET-1) in the kidneys of patients with diabetic nephropathy (DN) and to investigate their relationship with renal interstitial fibrosis (RIF). A total of 47 paraffin specimens of patients with DN and six controls were enrolled in this study, and all were diagnosed by histopathology. We studied the expressions of Ang-II, HIF-1α and ET-1 by immuno-histochemical staining and the level of RIF by Masson staining. The following results were found: (a) RIF existed in the kidneys of patients with DN, (b) the expressions of Ang-II, HIF-1α and ET-1 were lower in the control group but increased significantly in the DN group, (c) the expression of Ang-II, HIF-1α and ET-1 in tubular epithelial cells directly correlated with RIF (r s = 0.659, 0.633, 0.716, P <0.01) and (d) the expression of Ang-II, ET-1 and HIF-1α in the kidneys of patients with DN positively correlated with serum creatinine (Scr) levels (r s = 0.391, 0.594, 0.531, P <0.01) but they did not correlate with the 24-h urinary protein, blood glucose and serum albumin levels. These results provide new insights suggesting that over-expression of Ang-II, HIF-1α and ET-1 promote the progression of RIF in DN. Thus, targeting reduction in the expression of Ang-II, HIF-1α and ET-1 can delay RIF in DN. Further studies are needed to validate this observation.

Topics: Adult; Aged; Angiotensin II; Diabetic Nephropathies; Disease Progression; Endothelin-1; Female; Fibrosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Male; Middle Aged; Nephritis, Interstitial

To investigate the effect of angiotensin II AT1 receptor blocker valsartan on hypoxia-inducible factor (HIF)-1α-mediated gene activation and its association with renal interstitial fibrosis (RIF) in diabetic nephropathy rats.. Sprague-Dawley rats were randomly divided into 3 groups: control (C group), streptozocin-induced diabetic nephropathy (D group), and valsartan-treated D rats (T group). At end of the 4th, 8th and 12th week 6 rats from each group were sacrificed and blood, urine and kidneys were collected. Blood glucose, serum creatinine (Scr) and 24-h urinary protein were measured and kidneys were processed for Masson-stain as well as immunohistochemistry and real time-PCR analyses of the expressions of HIF-1α, and its target genes tissue inhibitor of metalloproteinase (TIMP)-1 and endothelin (ET)-1 in the kidney.. (1) At the 4th, 8th and 12th week, the areas of RIF were significantly increased in D and T groups, which was accompanied by higher levels of 24-h urinary protein, Scr, HIF-1α, ET-1 and TIMP-1 compared with C group. (2) At the 8th and 12th week, the above changes were significantly attenuated in T group compared with D group.. Valsartan may reduce HIF-1α-mediated gene activation and consequently improve kidney damage in diabetic nephropathy rats.

Topics: Animals; Blood Glucose; Blotting, Western; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelin-1; Gene Expression; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Male; Nephritis, Interstitial; Proteinuria; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Streptozocin; Tetrazoles; Tissue Inhibitor of Metalloproteinase-1; Valine; Valsartan

This study was designed to evaluate the possible renoprotective effects of rosiglitazone (RGT), a peroxisome proliferator-activated subtype gamma receptor agonist, in deoxycorticosterone acetate (DOCA)-salt hypertension and its role in endogenous endothelin-1 (ET-1) production and renal fibrosis associated with inflammation. Rats were implanted with DOCA strips (200 mg kg(-1)) at 1 week after unilateral nephrectomy. DOCA-salt rats received control diet with or without RGT (10 mg kg(-1) per day). Systolic blood pressure was measured by the tail-cuff method. Glomerulosclerosis and tubulointerstitial fibrosis were evaluated on kidney sections. The expression of ED-1, cyclooxygenase-2 (COX-2), heat shock protein-25 (HSP25) and transforming growth factor-beta1 (TGF-beta1) was determined in the kidney by semiquantitative immunoblotting. In DOCA-salt rats, systolic blood pressure was increased, whereas creatinine clearance decreased compared with controls, which were counteracted by RGT treatment. Tubular injury and glomerulosclerois in the histological study were prominent in DOCA-salt rats, which were counteracted by RGT treatment. ET-1 expression was increased in DOCA-salts rats, which was attenuated by RGT treatment. The expression of TGF-beta1, ED-1 and COX-2 was increased in DOCA-salt, which was attenuated by RGT treatment. In conclusion, RGT treatment decreases blood pressure and is effective in preventing the progression of renal injury in DOCA-salt hypertension, the mechanisms of which are associated with anti-inflammatory and anti-fibrotic effects through reducing the overexpression of ET-1, ED-1, COX-2 and TGF-beta1 in the kidney.

Topics: Animals; Cyclooxygenase 2; Desoxycorticosterone; Disease Models, Animal; Endothelin-1; Glomerulonephritis; HSP27 Heat-Shock Proteins; Hypertension; Kidney; Male; Nephritis, Interstitial; PPAR gamma; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones; Transforming Growth Factor beta1

Ghrelin is a novel 28 amino acid growth hormone-releasing peptide hormone that has been shown to inhibit cell proliferation and to decrease the production of proinflammatory cytokines by monocytes/macrophages. Moreover it decreases the release of endothelin-1 (ET-1), as well as mononuclear cell binding.. Seventeen patients with proliferative glomerulopathies (PG) and 15 patients with non-proliferative glomerulopathies (NPG) were examined by percutaneous renal biopsy. As a control 11 biopsy specimens of the kidneys removed because of trauma were used. The immunoexpression of ghrelin and ET-1 was assessed semiquantitatively whereas the interstitial monocytes/macrophages and interstitial area were evaluated quantitatively.. The mean value of the immunoexpression of ghrelin was significantly diminished in PG patients as compared to both NPG group and controls while the mean values of ET-1, interstitial CD68+ cells, as well as interstitial area were in PG group increased in comparison with controls and NPG patients, most of them significantly. In all groups there were significant negative correlations between immunostaining of ghrelin and ET-1, whereas negative correlation between immunostaining of ghrelin and CD68+ cells was significant only in PG group.. We can confirm the presence of ghrelin in tubular epithelial cells in normal and diseased human kidneys. Lack or low level of this protein in proliferative glomerulopathies may be, in part, responsible for interstitial accumulation of monocytes/macrophages in these cases.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Endothelin-1; Epithelial Cells; Female; Fibrosis; Ghrelin; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Humans; Immunoenzyme Techniques; Kidney Tubules; Macrophages; Male; Middle Aged; Monocytes; Nephritis, Interstitial; Young Adult

Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney; Nephritis, Interstitial; Receptor, Endothelin A; Receptor, Endothelin B; Renin; Renin-Angiotensin System; Systole

Secondary activation of the renin-angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2).. Ren2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague-Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1).. During the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P < 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P < 0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P < 0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P < 0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2.. ET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.

Topics: Acrylates; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Imidazoles; Kidney; Male; Metalloendopeptidases; Models, Cardiovascular; Nephritis, Interstitial; Organ Size; Osteopontin; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Renin; Renin-Angiotensin System; RNA, Messenger; Sialoglycoproteins; Systole; Thiophenes

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

Topics: Animals; Blood Pressure; Blotting, Northern; Body Constitution; Endothelin-1; Female; Gene Expression Regulation; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; In Situ Hybridization; Kidney Diseases, Cystic; Male; Mice; Mice, Transgenic; Nephritis, Interstitial; Organ Size; Potassium; Proteinuria; Renal Artery; Sodium

Cyclosporine nephrotoxicity is caused by renal arteriolar vasoconstriction and tubulointerstitial fibrosis. Endothelin has been proposed as a major mediator of these phenomena. Heparin inhibits vascular smooth muscle cell proliferation and lowers blood pressure by regulating endogenous endothelin 1 production. In a model of chronic cyclosporine nephrotoxicity in the rat, animals were treated with cyclosporine alone, cyclosporine plus heparin, and heparin alone for 28 days. Independent experiments determined that these doses of heparin resulted in a marked decrease in responsivity to exogenous endothelin. Despite this, there were no beneficial effects on renal structure or function in this animal model of chronic cyclosporine nephrotoxicity. Thus, the role of endothelin in the pathogenesis of the chronic tubulointerstitial changes and arteriolopathy in this model is probably minor.

Topics: Animals; Arterioles; Blood Pressure; Cyclosporine; Endothelin-1; Fibrosis; Heparin; Immunosuppressive Agents; Kidney; Kidney Tubules; Male; Nephritis, Interstitial; Rats; Rats, Wistar