cyclic-gmp and Acute-Kidney-Injury

Natriuretic peptides exert vasodilatory, natriuretic, and diuretic effects and inhibit renin and aldosterone secretion. Carperitide, a recombinant alpha-human atrial natriuretic peptide (hANP), is used for the treatment of cardiac failure. Patients with renal failure often require renal replacement therapy, and little is known about the pharmacokinetics of carperitide when used for renal replacement therapy.. Eleven patients who received continuous carperitide infusion and needed continuous venovenous hemofiltration (CVVHF) for acute renal failure were observed. The plasma hANP concentration was noted and the hANP clearance during CVVHF was calculated. The results indicated that infused hANP was removed by CVVHF. Although the clearance of hANP by CVVHF was relatively lower than the expected whole body clearance, CVVHF slightly reduced plasma hANP and cyclic guanosine monophosphate concentrations and increased arterial pressure.. CVVHF affects the pharmacology of infused hANP in critically ill patients. Some caution with respect to blood pressure may be necessary when carrying out CVVHF for critically ill patients receiving continuous infusion of natriuretic peptides.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Failure; Hemofiltration; Humans; Middle Aged; Recombinant Proteins

Ginkgo biloba (Gb) extracts have been used as a traditional Chinese medicine. Gb contains flavonoids, which are considered to be its active ingredients and have been used in the treatment of a variety of diseases. However, few scientific research studies on the side effects of flavonoid in Gb have been reported.. The present study aimed to investigate the effect of bilobetin on the kidney of Sprague-Dawley (SD) rats.. In this study, rats were injected with 50 mg/kg of bilobetin, a biflavone isolated from Gb, for 7 days and aristolochic acid was used as positive controls. The results showed that the body weight and urine output of the rats were dramatically decreased, and urinary protein increased after the intraperitoneal injection of bilobetin compared with the control group. Bilobetin treatment showed vacuolar degeneration in the renal tubular epithelium, glomerular atrophy by histostaining, and podocyte fusion by electron microscopy. This study further showed that bilobetin promoted the trafficking of aquaporin 2 (AQP-2) onto the plasma membrane to achieve the function of urine concentration by in vivo study in rats and in vitro study in IMCD-3 cells. The redistribution of AQP-2 is due to increased expression of cGMP in IMCD-3 cells, which in turn promoted the phosphorylation of AQP-2 at site Ser-256. The proteinuria caused by bilobetin may be attributed to podocyte cell cycle arrest at G2/M transition, which is may associated with AKT and MAPK signaling.. The current study showed that bilobetin has some side effects on kidneys at a dose of 50 mg/kg in SD rats and provides insight into the potential detrimental effects of monomeric ingredients in Gb.

Topics: Acute Kidney Injury; Animals; Aquaporin 2; Cell Cycle Checkpoints; Cell Line; Cell Membrane; Cyclic GMP; Drugs, Chinese Herbal; Flavonoids; Ginkgo biloba; HEK293 Cells; Humans; Kidney; Kidney Glomerulus; Male; Plant Extracts; Podocytes; Proteinuria; Rats, Sprague-Dawley

Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential.. We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI.. Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Apoptosis; Biomarkers; Blood Pressure; Cyclic GMP; Diuresis; Dogs; Glomerular Filtration Rate; Male; Natriuresis; Natriuretic Peptide, C-Type; Natriuretic Peptides; Receptors, Atrial Natriuretic Factor; Renal Agents; Renal Circulation

Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, L-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-β-D-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function.

Topics: Acute Kidney Injury; Animals; Arginine; Aristolochic Acids; Creatinine; Cyclic GMP; Kidney; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Polyuria; Proteinuria; Sodium; Superoxide Dismutase

Although atrial natriuretic peptide has been shown to attenuate ischemia-reperfusion (IR)-induced kidney injury, the effect of natriuretic peptide receptor (NPR)-B activation on IR-induced acute kidney injury is not well documented. The purpose of the present study was to identify the effect of C-type natriuretic peptide (CNP), a selective activator of NPR-B, on the IR-induced acute kidney injury and its mechanisms involved.. Unilaterally nephrectomized rats were insulted by IR in their remnant kidney, and they were randomly divided into three groups: sham, vehicle+IR, and CNP+IR groups. CNP (0.2μg/kg/min) was administered intravenously at the start of a 45-min renal ischemia for 2h. Rats were then killed 24h after I/R, and the blood and tissue samples were collected to assess renal function, histology, TUNEL assay, and Western blot analysis of kidney Bax and Bcl-2 expressions.. The levels of blood urea nitrogen and serum creatinine were significantly increased in rats after IR compared with vehicle-treated rats. IR elevated apoptosis, Bcl-2/Bax ratio, TUNEL positivity, oxidative stress parameters, malondialdehyde concentration, and superoxide dismutase activity. IR also induced epithelial desquamation of the proximal tubules and glomerular shrinkage. CNP significantly attenuated the IR-induced increase in BUN and serum creatinine. Furthermore, CNP restored the suppressed renal cyclic guanosine 3' 5'-monophosphate levels caused by IR insult.. Study findings suggest that CNP could ameliorate IR-induced acute kidney injury through inhibition of apoptotic and oxidative stress pathways, possibly through NPR-B-cGMP signaling.

Topics: Acute Kidney Injury; Animals; Apoptosis; bcl-2-Associated X Protein; Blood Urea Nitrogen; Blotting, Western; Creatinine; Cyclic GMP; In Situ Nick-End Labeling; Male; Malondialdehyde; Natriuretic Peptide, C-Type; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Reperfusion Injury; Signal Transduction; Superoxide Dismutase

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Biopsy; Cyclic GMP; Escherichia coli Infections; Histiocytes; Humans; Ischemia; Kidney; Kidney Diseases; Malacoplakia; Male; Middle Aged; Periodic Acid-Schiff Reaction; Postoperative Complications; Pyelonephritis; Transplants; Urinary Tract Infections

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

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-alpha and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 microl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-alpha (1.00 +/- 0.55 vs. 7.02 +/- 2.40 pg/ml, P < 0.05) and serum IL-1beta (31.3 +/- 3.6 vs. 53.3 +/- 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 microl/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 +/- 5.8 vs. 178.0 +/- 7.6 mmHg.ml(-1).min(-1), P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-alpha, IL-1beta, and NO as well as a decrease in renal iNOS and ICAM-1.

Topics: Acute Kidney Injury; Alprostadil; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Down-Regulation; Endotoxemia; Enzyme Inhibitors; Glomerular Filtration Rate; Intercellular Adhesion Molecule-1; Interleukin-1; Kidney Cortex; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pentoxifylline; Tumor Necrosis Factor-alpha

Acute endotoxemic renal failure involves renal vasoconstriction, which presumably occurs despite increased nitric oxide (NO) generation by inducible NO synthase in the kidney. The present study examined the hypothesis that the renal vasoconstriction during endotoxemia occurs in part because of desensitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shock and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manner, reaching the highest levels at 24 h, in parallel with induction of inducible NO synthase protein in the renal cortex. In renal cortical slices obtained from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 24 h after injection of lipopolysaccharide. Incubation of renal cortical slices in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cGMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. However, in slices from 24-h endotoxemic mice, accumulation of cGMP in response to sodium nitroprusside was significantly lower. This lower stimulability of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the associated renal vasoconstriction.

Topics: Acute Kidney Injury; Animals; Cyclic GMP; Endotoxemia; Enzyme Induction; Guanylate Cyclase; Kidney Cortex; Male; Mice; Mice, Inbred Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroprusside; Shock, Septic; Solubility

We examined the role of oxygen free radicals in cisplatin-induced acute renal failure (ARF). The intravenous injection of cisplatin (5 mg/kg body weight) induced an increase in serum creatinine and tubular damage in the outer stripe of the outer medulla in rats. The renal content of malondialdehyde (MDA) transiently increased. Treatment with the free radical scavengers dimethylthiourea (DMTU) or lecithinized superoxide dismutase (L-SOD) attenuated the increase in serum creatinine. The beneficial effect of DMTU, a hydroxyl radical scavenger, was associated with less accumulation of MDA, less tubular damage, and enhanced expression of proliferating cell nuclear antigen (PCNA) in the damaged tubular cells, but not with improvement of reduced renal blood flow (RBF). On the other hand, the beneficial effect of L-SOD, a superoxide anion scavenger, was associated with preservation of RBF and increased urinary guanosine 3',5'-cyclic monophosphate excretion but not with modification of tubular damage or PCNA expression. These results suggest that (1) cisplatin-induced nephrotoxicity was associated with lipid peroxidation, (2) the hydroxyl radical scavenger prevented ARF through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells, and (3) the superoxide anion scavenger did the same through preservation of RBF. It follows that oxygen free radicals may play an important role in cisplatin-induced ARF by reducing RBF and inducing tubular damage.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Cisplatin; Creatinine; Cyclic GMP; Free Radical Scavengers; Kidney Tubules; Lipid Peroxidation; Male; Malondialdehyde; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Renal Circulation; Superoxide Dismutase; Thiourea

Because myoglobin is a potent inhibitor of nitric oxide (NO), we tested whether myoglobin infusion results in renal vasoconstriction and dysfunction, on which L-arginine, a source of NO, has a protective effect in sedated, nondehydrated, and nonacidotic rabbits. The infusion of myoglobin (375 mg/kg) resulted in a decrease in renal blood flow, an increase in renal vascular resistance, and a decrease in creatine clearance associated with a decrease in urinary excretory rate of nitrite/nitrate and guanosine 3',5'-cyclic monophosphate (cGMP). These values 1-2 h after the infusion were significantly different from baseline levels. Co-administration of L-arginine (150 mg/kg bolus followed by 150 mg.kg(-1).min(-1) reversed these changes significantly with attenuation of urinary excretory rate of nitrite/nitrate and cGMP. This study suggests that the myoglobin-induced renal vasoconstriction and dysfunction and protective effect of L-arginine on these outcomes could be mediated through the NO system.

Topics: Acute Kidney Injury; Animals; Arginine; Creatinine; Cyclic GMP; Male; Myoglobin; Nitrates; Nitrites; Rabbits; Renal Circulation; Vascular Resistance

EDRF results from the metabolism of L-arginine. N-omega-nitro-L-arginine is a nitric oxide synthase inhibitor (L-arginine competitive inhibitor). Acute renal failure was induced by i.m glycerol (50%) 5 ml/kg bw. L-arginine: 3 mg/kg bw/min for 60 min before and 60 min after glycerol administration. L-arginine inhibitor (150 micrograms/kg bw/min for 120 min). Cin, Cpah and FENa% were measured immediately or 24 h after glycerol (mean of three periods of 20 min). A second series of similar experiments was done in dehydrated (16 h) rats with a high dose of glycerol (50% solution, 10 ml/kg bw). L-arginine ameliorates the severity of ARF immediately after glycerol administration and enhances the recovery of glycerol-induced ARF. The L-arginine inhibitor resulted in a more severe ARF. Urinary cGMP decreased significantly after glycerol administration. It is concluded that nitric oxide has an important pathogenetic role in the glycerol induced ARF.

Topics: Acute Kidney Injury; Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Cyclic GMP; Female; Glomerular Filtration Rate; Glycerol; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Renal Circulation

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Topics: Acute Kidney Injury; Animals; Arginine; Blood Pressure; Cyclic GMP; Diatrizoate; Female; Nitrates; Nitric Oxide; Nitrites; Nitroarginine; Rats; Rats, Sprague-Dawley; Sodium; Time Factors

To investigate the increase in plasma cyclic GMP (cGMP) concentrations in humans with hyperkinetic septic shock (SS) and to evaluate its relationship to low systemic vascular resistance (SVR).. Prospective clinical investigation.. Medical intensive care unit of a university hospital.. 22 patients with documented SS requiring hemodynamic resuscitation, respiratory support and--in some cases--hemodialysis.. Hemodynamic data were recorded at admission time and then twice a-day during the following 72 h. We simultaneously measured cyclic GMP, atrial natriuretic peptides (ANP), creatininemia and platelet counts. At admission time, higher plasma cGMP concentrations were observed in patients with SS (11.84 +/- 1.52 pmol.ml-1) than in healthy controls (1.77 +/- 0.18 pmol.ml-1, p < 0.0001), in septicemia patients without circulatory failure (3.28 +/- 0.36 pmol.ml-1, p < 0.005) or in patients with hyperkinetic non-septic shock (3.6 +/- 0.7 pmol.ml-1, p < 0.02). In contrast, there was no significant difference between patients with SS and controls with anuria from non-septic origin. Also ANP concentrations were higher in patients with SS than in others. In addition, cGMP levels correlated negatively with SVR during the first 48 h of the study, and positively with creatininemia later when renal function worsened. However, they did not correlate significantly with ANP.. These data demonstrate that a significant increase in plasma cGMP concentrations occurs during human SS and that it correlates with the decline in peripheral vascular resistance in the absence, but not in the presence, of severe renal failure. Furthermore, the increase in cGMP levels cannot be ascribed solely to enhanced ANP-induced particulate guanylyl cyclase activity. Thus, our results suggest the occurrence of another endogenous source of cGMP during hyperkinetic SS.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Female; Humans; Male; Middle Aged; Platelet Count; Prospective Studies; Shock, Septic; Vascular Resistance

Structure/activity studies on atrial natriuretic peptide ANP (1-28) have highlighted three portions of the native molecule as necessary for its biological responses. We have linked these three regions and excised the remaining segments to produce a family of small analogues (less than half the size of the parent) which demonstrate the full range of ANP's actions. Importantly, these compounds act at both major types of ANP receptor. Two critical modifications lead to more potent analogues; both involve expanding the cyclic portion of the molecule. Further optimization of one of these modified structures leads to A68828, a full ANP agonist which shows promise as a preventative agent against acute renal failure.

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Binding, Competitive; Cyclic GMP; Diuresis; Dogs; Enzyme Activation; Guanylate Cyclase; Male; Molecular Sequence Data; Natriuresis; Peptide Fragments; Rabbits; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Structure-Activity Relationship

In twelve patients with acute renal failure, mean plasma levels of atrial natriuretic factor (ANF) and of its second messenger cGMP were found elevated at the early phase of the disease, but tended to return towards normal values at recovery. Variations of plasma ANF and cGMP were correlated significantly (p less than 0.05) with those of total blood volume. At the early phase of the disease, plasma ANF was also correlated with the excreted fraction of filtered sodium (FENa) (r = 0.95). Moreover, plasma ANF and FENa peaked concomitantly at the onset of the diuretic phase in the five patients who were not treated by diuretics or dialysis and were studied sequentially during the course of the disease. It is suggested that enhanced plasma ANF levels might reflect one of the mechanisms of adaptation controlling body fluid balance in acute renal failure.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Female; Humans; Male; Middle Aged; Prognosis; Sodium