title: Spironolactone improves nephropathy by enhancing glucose-6-phosphate dehydrogenase activity and reducing oxidative stress in diabetic hypertensive rat.
abstract: Spironolactone (SPR), a mineralocorticoid receptor blocker, diminishes hyperglycemia-induced reduction in glucose-6-phosphate dehydrogenase (G6PD) activity, improving oxidative stress damage. This study investigated whether SPR ameliorates nephropathy by increasing G6PD activity and reducing oxidative stress in spontaneously hypertensive diabetic rats (SHRs). The streptozotocin-induced diabetic rats received or not SPR 50 mg/kg per day, for eight weeks. A human mesangial cell line was cultured in normal or high glucose conditions, with or without SPR, for 24 h. Plasma glucose levels and systolic blood pressure were unaltered by diabetes or by SPR treatment. Albuminuria, fibronectin expression, 8-OHdG urinary levels, lipid peroxidation and p47phox expression were higher in the diabetic rats compared with the control and were reduced by SPR. The antioxidant GSH/GSSG ratio was reduced in the diabetic rats and the treatment reestablished it. Diabetes-induced SGK1 up-regulation was inhibited by SPR. Reactive oxygen species (ROS) and superoxide production induced by NADPH oxidase were increased by hyperglycemia and high glucose, in vivo and in vitro, respectively, and were reduced with SPR. Hyperglycemia and high glucose decreased G6PD activity, which was restored with SPR. These results suggest that SPR ameliorates nephropathy in diabetic SHRs by restoring G6PD activity and diminishes oxidative stress without affecting glycaemia and blood pressure.
authors: Department of Internal Medicine, Renal Pathophysiology Laboratory, Investigation in Diabetes Complications, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors: Bruno S
authors: BS
authors: Pessôa
authors: Elisa B M I
authors: EB
authors: Peixoto
authors: Alexandros
authors: A
authors: Papadimitriou
authors: Jacqueline M
authors: JM
authors: Lopes de Faria
authors: José B
authors: JB
authors: Lopes de Faria
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D005954:Glucosephosphate Dehydrogenase; D019803:Glutathione Disulfide; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D009249:NADP; D019255:NADPH Oxidases; D016877:Oxidants; D017346:Protein Serine-Threonine Kinases; D013148:Spironolactone; D013481:Superoxides; D000099184:Serum-Glucocorticoid Regulated Kinases; C060505:neutrophil cytosolic factor 1