螺内酯通过抑制 ROS 产生抑制高血糖诱导的足细胞损伤。
Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.
机构信息
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
出版信息
Nephrol Dial Transplant. 2011 Aug;26(8):2475-84. doi: 10.1093/ndt/gfq750. Epub 2011 Jan 10.
BACKGROUND
Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy although the renin-angiotensin-aldosterone system is generally suppressed in diabetes. The present study was designed to confirm the antiproteinuric effect of MR blockade in diabetic rats and elucidate its mechanism.
METHODS
The present study investigated whether MR blockade inhibits hyperglycemia-induced podocyte injury, focusing on the involvement of reactive oxygen species (ROS) production, in diabetic rats and cultured podocytes. Sprague-Dawley rats were divided into three groups: control, streptozotocin (STZ; 75 mg/kg)-injected diabetic and STZ treated with spironolactone (SPL; 50 mg/kg/day) and sacrificed after 8, 16 and 24 weeks.
RESULTS
Rats gradually developed proteinuria from 8 weeks after induction of diabetes. Immunostaining for Wilms' tumor-1 (WT1) and synaptopodin, markers of podocytes, was attenuated, whereas immunostaining for desmin, a marker of podocyte damage, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, was up-regulated in the glomeruli of diabetic rats. Diabetic rats showed hypoaldosteronemia compared to the control, whereas SPL decreased proteinuria, ROS production and podocyte damage. To elucidate the paradox between hypoaldosteronemia and effect of SPL under hyperglycemia, the role of high glucose in MR activation and podocyte injury was explored. In cultured MR-expressing podocytes, high glucose significantly enhanced Sgk1 expression, activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS production and induced podocyte apoptosis. All these effects were inhibited by SPL.
CONCLUSION
We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.
背景
越来越多的证据表明，尽管糖尿病中肾素-血管紧张素-醛固酮系统通常受到抑制，但盐皮质激素受体（MR）阻断可有效减少糖尿病肾病的蛋白尿。本研究旨在证实 MR 阻断在糖尿病大鼠中的抗蛋白尿作用，并阐明其机制。
方法
本研究通过观察活性氧（ROS）的产生，探讨了 MR 阻断是否抑制高血糖诱导的足细胞损伤，重点研究了这一过程在糖尿病大鼠和培养的足细胞中的作用。将 Sprague-Dawley 大鼠分为三组：对照组、链脲佐菌素（STZ；75mg/kg）注射的糖尿病组和用螺内酯（SPL；50mg/kg/天）治疗的 STZ 处理组，并在诱导糖尿病 8、16 和 24 周后处死。
结果
大鼠在诱导糖尿病后 8 周逐渐出现蛋白尿。Wilms' 肿瘤-1（WT1）和突触蛋白的免疫染色减弱，而足细胞损伤的标志物 desmin 和氧化应激的标志物 8-羟基-2'-脱氧鸟苷的免疫染色增强。与对照组相比，糖尿病大鼠表现出低醛固酮血症，而 SPL 降低了蛋白尿、ROS 产生和足细胞损伤。为了阐明高血糖下低醛固酮血症和 SPL 作用之间的矛盾，研究了高糖在 MR 激活和足细胞损伤中的作用。在表达 MR 的培养足细胞中，高葡萄糖显著增强了 Sgk1 的表达，激活了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和 ROS 的产生，并诱导了足细胞凋亡。所有这些作用都被 SPL 抑制。
结论
我们的结论是，糖尿病中的高血糖，独立于血浆醛固酮浓度，通过 MR 介导的 ROS 产生诱导足细胞损伤，导致蛋白尿。SPL 通过抑制 ROS 产生来抑制高血糖诱导的足细胞损伤。
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