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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / metabolism
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Biomarkers / metabolism
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DNA Damage
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / enzymology*
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Diabetes Mellitus, Experimental / pathology*
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Diabetic Nephropathies / complications
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Diabetic Nephropathies / drug therapy*
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Diabetic Nephropathies / enzymology*
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Diabetic Nephropathies / pathology
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Glucosephosphate Dehydrogenase / antagonists & inhibitors
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Glucosephosphate Dehydrogenase / metabolism*
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Glutathione Disulfide / metabolism
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Humans
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Immediate-Early Proteins / metabolism
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Kidney Cortex / drug effects
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Kidney Cortex / enzymology
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Kidney Cortex / pathology
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Lipid Peroxidation / drug effects
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Mesangial Cells / drug effects
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Mesangial Cells / enzymology
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Mesangial Cells / pathology
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Mineralocorticoid Receptor Antagonists / pharmacology
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Mineralocorticoid Receptor Antagonists / therapeutic use
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Models, Biological
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NADP / metabolism
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NADPH Oxidases / metabolism
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Oxidants / metabolism
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Oxidative Stress* / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Rats, Inbred SHR
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Spironolactone / pharmacology
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Spironolactone / therapeutic use*
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Superoxides / metabolism
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Up-Regulation / drug effects
Substances
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Antioxidants
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Biomarkers
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Immediate-Early Proteins
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Mineralocorticoid Receptor Antagonists
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Oxidants
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Superoxides
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Spironolactone
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NADP
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Glucosephosphate Dehydrogenase
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NADPH Oxidases
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neutrophil cytosolic factor 1
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Protein Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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Glutathione Disulfide