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.

Antioxidant N-Acetylcysteine Protects Pancreatic β-Cells Against Aldosterone-Induced Oxidative Stress and Apoptosis in Female db/db Mice and Insulin-Producing MIN6 Cells

“…Although urinary 8-OHdG was observed to be partially decreased after SPL treatment (38), SPL had no effect on the expression of Bcl-2/Bax, p-AKT/total AKT protein, iNOS, NADPH oxidase, p22phox, and p67phox in db/db mice islets or MIN6 cells. This indicates that SPL has limited antioxidant activity.…”

The effects of aldosterone on diet-induced fatty liver formation in male C57BL/6 mice

“…Some previous reports have shown that MRBs exerted no beneficial effects or even led to the aggravation of hyperglycemia and metabolic syndrome [5][6][7][8][9][10], but other studies have shown that spironolactone treatment ameliorated insulin resistance in obese mice or in diet-induced metabolic syndrome [11,12]. Some previous reports have shown that MRBs exerted no beneficial effects or even led to the aggravation of hyperglycemia and metabolic syndrome [5][6][7][8][9][10], but other studies have shown that spironolactone treatment ameliorated insulin resistance in obese mice or in diet-induced metabolic syndrome [11,12].…”

Therapeutic Insights against Oxidative Stress Induced Diabetic Nephropathy: A Review

“…Researches are being focused on targeting different T-regulatory cells which can suppress pro-inflammatory response via attenuation of respective signalling cascades. Experiments on different animal models have demonstrated their efficacy in treating oxidative stress induced DN [184]. Interestingly, studies on human with some of these molecules have also shown positive results.…”

“…SPL exposure has shown to down regulate TGF-β expression and hence it inhibits oxidative stress in renal cortex of diabetic rats [183]. Therefore, it can be said that SPL can function as an antioxidant compound by elevating anti-oxidative defense systems (like GSH level) and thereby reducing oxidative stress [184]. However, the limitation of SPL administration is that its protective action is effective at early stages of DN but it has no beneficial effect at later stages of the disease [185,186].…”