Department of Internal Medicine, Renal Pathophysiology Laboratory, Investigation in Diabetes Complications, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
J Renin Angiotensin Aldosterone Syst. 2012 Mar;13(1):56-66. doi: 10.1177/1470320311422581. Epub 2011 Oct 10.
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.
螺内酯（SPR）是一种盐皮质激素受体阻滞剂，可减轻高血糖引起的葡萄糖-6-磷酸脱氢酶（G6PD）活性降低，从而改善氧化应激损伤。本研究探讨了螺内酯是否通过增加 G6PD 活性和减少自发性高血压糖尿病大鼠（SHRs）的氧化应激来改善肾病。用链脲佐菌素诱导糖尿病大鼠，每天给予或不给予 SPR50mg/kg，持续 8 周。在正常或高葡萄糖条件下培养人肾小球系膜细胞系，有或没有 SPR，持续 24 小时。糖尿病或 SPR 治疗对血浆葡萄糖水平和收缩压没有影响。与对照组相比，糖尿病大鼠的白蛋白尿、纤维连接蛋白表达、8-OHdG 尿水平、脂质过氧化和 p47phox 表达更高，而 SPR 则降低了这些指标。糖尿病大鼠的抗氧化 GSH/GSSG 比值降低，而治疗则恢复了该比值。SPR 抑制了糖尿病诱导的 SGK1 上调。NADPH 氧化酶诱导的活性氧（ROS）和超氧化物产生在体内和体外分别增加了高血糖和高葡萄糖，而 SPR 则降低了它们。高血糖和高葡萄糖降低了 G6PD 活性，而 SPR 则恢复了其活性。这些结果表明，SPR 通过恢复 G6PD 活性并减轻氧化应激而改善糖尿病 SHRs 的肾病，而不影响血糖和血压。
