stilbenes and Proteinuria

High fructose is considered a causative factor for oxidative stress and autophagy imbalance that cause kidney pathogenesis. Antioxidant polydatin isolated from Polygonum cuspidatum has been reported to protect against kidney injury. In this study, polydatin was found to ameliorate fructose-induced podocyte injury. It activated mammalian target of rapamycin complex 1 (mTORC1) and suppressed autophagy in glomeruli of fructose-fed rats and in fructose-exposed conditionally immortalized human podocytes (HPCs). Polydatin also enhanced nuclear factor-E2-related factor 2 (Nrf2)-dependent antioxidant capacity to suppress fructose-induced autophagy activation in vivo and in vitro, with the attenuation of fructose-induced up-regulation of cellular light chain 3 (LC3) II/I protein levels. This effect was abolished by Raptor siRNA in fructose-exposed HPCs. These results demonstrated that polydatin ameliorated fructose-induced autophagy imbalance in an mTORC1-dependent manner via improving Nrf2-dependent antioxidant capacity during podocyte injury. In conclusion, polydatin with anti-oxidation activity suppressed autophagy to protect against fructose-induced podocyte injury.

Topics: Adenosine Triphosphate; Adenylate Kinase; Animals; Antioxidants; Autophagy; Feeding Behavior; Fructose; Glucosides; Homeostasis; Humans; Male; Mechanistic Target of Rapamycin Complex 1; NF-E2-Related Factor 2; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Podocytes; Proteinuria; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Preeclampsia (PE) and fetal growth restriction (FGR) contribute significantly to fetal and maternal morbidity and mortality. Although the causes of PE and FGR are not fully understood, both conditions are known to be associated with impaired uterine artery blood flow. Resveratrol, a polyphenol found in a number of plants, has been shown to induce relaxation of uterine arteries in vitro as well as improve many pathological conditions associated with PE and FGR. We hypothesized that treatment of endothelial nitric oxide synthase knockout mice (eNOS⁻/⁻) and catechol-O-methyltransferase knockout mice (COMT⁻/⁻) with resveratrol during pregnancy would improve uterine artery blood flow and therefore ameliorate the PE-like phenotype and FGR in these murine models. Pregnant C57BL/6J, eNOS⁻/⁻ and COMT⁻/⁻ mice received either resveratrol supplemented diet (4 g/kg diet) or control diet between gestational day (GD) 0.5 and GD 18.5. Resveratrol supplementation significantly increased uterine artery blood flow velocity and fetal weight in COMT⁻/⁻ but not in eNOS⁻/⁻ mice. There were no effects of resveratrol on litter size and placental weight among the groups. In conclusion, resveratrol increased uterine artery blood flow velocity and fetal weight in COMT⁻/⁻ mice, suggesting potential as a therapeutic strategy for PE and FGR.

Topics: Analysis of Variance; Animals; Blood Flow Velocity; Blood Pressure; Catechol O-Methyltransferase; Female; Fetal Growth Retardation; Fetal Weight; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Acoustic; Nitric Oxide Synthase Type III; Pre-Eclampsia; Pregnancy; Proteinuria; Regional Blood Flow; Resveratrol; Stilbenes; Uterus

Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS; 300 μg/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K(+) output and the decrease in urine osmolality, Na(+) output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Antihypertensive Agents; Aorta; Aryl Hydrocarbon Hydroxylases; Blood Pressure; Cardiomegaly; Cytochrome P-450 CYP1B1; Desoxycorticosterone; Disease Models, Animal; Diuresis; Endothelium, Vascular; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Hypertension; Kidney; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocardium; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; p38 Mitogen-Activated Protein Kinases; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Stilbenes; Superoxides; Time Factors; Vasoconstriction; Vasodilation

Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.

Topics: Animals; Antineoplastic Agents; Antioxidants; Cisplatin; Creatinine; Drug Therapy, Combination; Ectodysplasins; Kidney Tubular Necrosis, Acute; Kidney Tubules; Macrophages; Male; Monocytes; Proteinuria; Rats; Rats, Wistar; Resveratrol; Stilbenes; T-Lymphocytes; Urination

Nitric oxide (NO) plays an important role in the modulation of glomerular disease. The renal protective effect of resveratrol (RVT), a polyphenolic phytoalexin, was investigated in the 5/6th nephrectomized rats.. Resveratrol (5 mg/kg, PO) was administered for 12 weeks to 5/6th nephrectomized (NX) rats together with and without nitro L-arginine methyl ester (L-NAME) (10 mg/kg, IP). We evaluated the effect of these agents on proteinuria, hypertension, renal function, glomerulosclerosis, and urinary excretion of nitric oxide metabolites.. 5/6th NX resulted in elevation in systolic blood pressure (SBP), reduced the urinary excretion of NO metabolites, increased urinary protein excretion, and deranged renal function and glomerulosclerosis. Treatment of animals with resveratrol significantly attenuated the increase in SBP, preserved the normal renal function, reduced the urinary protein excretion, increased the urinary excretion of NO metabolites, and prevented the glomerulosclerosis. Co-administration of animals with L-NAME along with resveratrol prevented the protection observed with resveratrol.. These findings indicate that resveratrol exerts its protective effect in 5/6 NX rats through a nitric oxide pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Pressure; Body Weight; Disease Models, Animal; Eating; Enzyme Inhibitors; Kidney Function Tests; Male; Nephrectomy; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Resveratrol; Stilbenes; Survival Rate

The effect of resveratrol, a polyphenolic compound present in grapes and other plants, on proteinuria, hypoalbuminemia and hyperlipidemia was studied in rats with glomerulonephritis. The nephritis was induced by an intravenous injection of anti-rat kidney glomerular basement membrane rabbit antiserum. Nephritic rats were given oral intubation of resveratrol (5 mg/day/100 g body weight) for 14 days, while control nephritic rats as well as normal ones were similarly given vehicle alone. By resveratrol treatment, enlargement in liver and kidney due to nephritis induction was significantly reduced, together with partial restoration of nephritis-induced reduction in body weight gain. Both proteinuria and hypoalbuminemia, characteristic symptoms to nephrotic syndrome, were significantly remedied, that is, urinary protein excretion was suppressed and serum albumin concentration was increased by resveratrol treatment. Resveratrol also suppressed significantly hyperlipidemia incident to nephritis, the hypotriglyceridemic action being more prominent than the hypocholesterolemic one. From these results, resveratrol is suggested to be a potent anti-glomerulonephritic food factor capable of suppressing proteinuria, hypoalbuminemia and hyperlipidemia at the same time.

Topics: Administration, Oral; Albumins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Basement Membrane; Blood Urea Nitrogen; Body Weight; Cholesterol; Disease Models, Animal; Eating; Glomerulonephritis; Hyperlipidemias; Hypoproteinemia; Kidney; Kidney Glomerulus; Liver; Male; Organ Size; Proteinuria; Rabbits; Rats; Rats, Wistar; Resveratrol; Stilbenes; Triglycerides