3-nitrotyrosine and Renal-Insufficiency

Parquetina nigrescens is commonly used to treat diseases in humans and animals in developing countries, including Nigeria. This study evaluates the effects of its polyphenol-rich fraction (prf) on dichlorvos-induced cardio- and renal toxicity. There were several factors assessed during this study, including cardiac and renal markers, serum myeloperoxidase and xanthine oxidase, and electrocardiograph (ECG) changes. The changes in electrocardiograph (ECG) were recorded. Immunohistochemistry of cardiac and renal p38 and nitrotyrosine was determined. Dichlorvos exposure caused a significant decrease in L-glutathione (reduced glutathione) and other antioxidant enzymes with increases in malondialdehyde, myeloperoxidase, advanced oxidation protein products, and protein carbonyl levels. It also brought about alterations in microanatomy of the heart and kidneys accompanied by increases in serum creatinine and urea levels. Exposure to dichlorvos induced prolonged QRS interval and shortened QT durations in rats. Immunohistochemistry revealed lower expressions of cardiac nitrotyrosine and renal p38 (mitogen-activated protein kinase; MAPK) in rats treated with prf of P. nigrescens. Combining all, prf of P. nigrescens demonstrated antioxidant as well as protective properties in the heart and kidneys of rats exposed to dichlorvos. It ameliorated dichlorvos-induced cardio- and nephrotoxicity giving credence to its use in ethnomedicine.

Topics: Administration, Oral; Animals; Biomarkers; Cryptolepis; Dichlorvos; Dietary Supplements; Heart Ventricles; Insecticides; Kidney; Male; Nigeria; Organophosphate Poisoning; p38 Mitogen-Activated Protein Kinases; Plant Components, Aerial; Plant Extracts; Polyphenols; Protective Agents; Random Allocation; Rats, Wistar; Renal Insufficiency; Tyrosine; Ventricular Dysfunction

Obesity-associated nephropathy is considered to be a leading cause of end-stage renal disease. Resveratrol supplementation represents a promising therapy to attenuate kidney injury, but the poor solubility and limited bioavailability of this polyphenol limits its use in dietary intervention. Piceatannol, a resveratrol analogue, has been suggested as a better option. In this study, we aimed to provide evidence of a preventive action of piceatannol in very early stages of obesity-associated nephropathy. Thirty obese Zucker rats were divided into three experimental groups: one control and two groups orally treated for 6 weeks with 15 and 45 mg piceatannol/kg body weight/day. Enzyme-linked immunosorbent assays (ELISA) were used to determine renal and urinary kidney injury molecule-1 (Kim-1), renal fibrosis markers (transforming growth factor β1 and fibronectin) and renal sirtuin-1 protein. Oxidative stress was assessed in the kidney by measuring lipid peroxidation and nitrosative stress (thiobarbituric acid reactive substrates and 3-nitrotyrosine levels, respectively) together with the activity of the antioxidant enzyme superoxide dismutase. Renal fatty acids profile analysis was performed by thin-layer and gas chromatography. Piceatannol-treated rats displayed lower levels of urinary and renal Kim-1. Renal fibrosis biomarkers and lipid peroxidation exhibited a tendency to decrease in the piceatannol-treated groups. Piceatannol treatment did not modify superoxide dismutase activity or sirtuin-1 protein levels, while it seemed to increase the levels of polyunsaturated and omega-6 polyunsaturated fatty acids in the kidneys. Our findings suggest a mild renoprotective effect of piceatannol in obese Zucker rats and the need of intervention at early stages of renal damage.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Cell Adhesion Molecules; Dietary Supplements; Fibrosis; Kidney; Lipid Peroxidation; Male; Obesity; Organ Size; Oxidative Stress; Random Allocation; Rats, Zucker; Renal Insufficiency; Severity of Illness Index; Stilbenes; Thiobarbituric Acid Reactive Substances; Tyrosine

Diabetic nephropathy is a serious complication of longstanding diabetes and its pathogenesis remains unclear. Oxidative stress may play a critical role in the pathogenesis and progression of diabetic nephropathy. Our previous studies have demonstrated that polyunsaturated fatty acids (PUFA) induce peroxynitrite generation in primary human kidney mesangial cells and heat shock protein 90β1 (hsp90β1) is indispensable for the PUFA action. Here we investigated the effects of high fat diet (HFD) on kidney function and structure of db/db mice, a widely used rodent model of type 2 diabetes. Our results indicated that HFD dramatically increased the 24 h-urine output and worsened albuminuria in db/db mice. Discontinuation of HFD reversed the exacerbated albuminuria but not the increased urine output. Prolonged HFD feeding resulted in early death of db/db mice, which was associated with oliguria and anuria. Treatment with the geldanamycin derivative, 17-(dimethylaminoehtylamino)-17-demethoxygeldanamycin (17-DMAG), an hsp90 inhibitor, preserved kidney function, and ameliorated glomerular and tubular damage by HFD. 17-DMAG also significantly extended survival of the animals and protected them from the high mortality associated with renal failure. The benefit effect of 17-DMAG on renal function and structure was associated with a decreased level of kidney nitrotyrosine and a diminished kidney mitochondrial Ca(2+) efflux in HFD-fed db/db mice. These results suggest that hsp90β1 is a potential target for the treatment of nephropathy and renal failure in diabetes.

Topics: Animals; Benzoquinones; Calcium; Diabetic Nephropathies; Diet, High-Fat; Disease Models, Animal; HSP90 Heat-Shock Proteins; Kaplan-Meier Estimate; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules; Lactams, Macrocyclic; Male; Mice; Mice, Knockout; Mitochondria; Renal Insufficiency; Tyrosine

Gentamicin is an antibiotic effective against Gram-negative infection, whose clinical use is limited by its nephrotoxicity. Oxygen free radicals are considered to be important mediators of gentamicin-mediated nephrotoxicity, but the exact nature of the radical in question is not known with certainty. We have investigated the potential role of superoxide in gentamicin-induced renal toxicity by using M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic, which selectively removes superoxide. Administration of gentamicin at 100 mg/kg, s.c. for 5 days to rats induced a marked renal failure, characterised by a significant decrease in creatinine clearance and increased plasma creatinine levels, fractional excretion of sodium, lithium, urine gamma glutamyl transferase (gamma GT) and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was also observed in gentamicin-treated rats. M40403 (10 mg/kg, i.p. for 5 days) attenuated all these parameters of damage. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose) synthetase (PARS) activation in the proximal tubule of gentamicin-treated rats. Renal histology examination confirmed tubular necrosis. M40403 significantly prevented gentamicin-induced nitrotyrosine formation, poly(ADP-ribose) synthetase activation and tubular necrosis. These results confirm our hypothesis that superoxide anions play an important role in gentamicin-mediated nephropathy and support the possible clinical use of low molecular weight synthetic superoxide dismutase mimetics in those conditions that are associated with over production of superoxide.

Topics: Animals; Anti-Bacterial Agents; Enzyme Activation; Free Radical Scavengers; Gentamicins; Kidney; Lipid Peroxidation; Male; Manganese; Molecular Mimicry; Neutrophil Infiltration; Organometallic Compounds; Oxidants; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Renal Circulation; Renal Insufficiency; Superoxide Dismutase; Superoxides; Tyrosine

Studies were performed on the mechanisms of the protective effects of free-radical scavengers against gentamicin-mediated nephropathy. Administration of gentamicin, 100 mg/kg s.c., for 5 days to rats induced marked renal failure, characterised by a significantly decreased creatinine clearance and increased blood creatinine levels, fractional excretion of sodium Na(+), lithium Li(+), urine gamma glutamyl transferase and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was observed in gentamicin-treated rats. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose)synthase activation in the proximal tubule from gentamicin-treated rats. Renal histology examination confirmed the tubular necrosis. N-acetylcysteine (10 mg/kg i.p. for 5 days) caused normalisation of the above biochemical parameters. In addition, N-acetylcysteine treatment significantly prevents the gentamicin-induced tubular necrosis. These results suggest that (1) N-acetylcysteine has protective effects on gentamicin-mediated nephropathy, and (2) the mechanisms of the protective effects can be, at least in part, related to interference with peroxynitrite-related pathways.

Topics: Acetylcysteine; Animals; Free Radical Scavengers; Gentamicins; Kidney; Male; Malondialdehyde; Peroxidase; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Tyrosine