Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and NOX4 is up‐regulated in podocytes in response to high glucose. In the present study, the effects of Salvianolate on DN and its underlying mechanisms were investigated in diabetic db/db mice and human podocytes. We confirmed that the Salvianolate administration exhibited similar beneficial effects as the NOX1/NOX4 inhibitor GKT137831 treated diabetic mice, as reflected by attenuated albuminuria, reduced podocyte loss and mesangial matrix accumulation. We further observed that Salvianolate attenuated the increase of Nox4 protein, NOX4‐based NADPH oxidase activity and restored podocyte loss in the diabetic kidney. In human podocytes, NOX4 was predominantly localized to mitochondria and Sal B treatment blocked HG‐induced mitochondrial NOX4 derived superoxide generation and thereby ameliorating podocyte apoptosis, which can be abrogated by AMPK knockdown. Therefore, our results suggest that Sal B possesses the reno‐protective capabilities in part through AMPK‐mediated control of NOX4 expression. Taken together, our results identify that Salvianolate could prevent glucose‐induced oxidative podocyte injury through modulation of NOX4 activity in DN and have a novel therapeutic potential for DN.

中文翻译：

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丹参多酚酸盐通过调节 db/db 小鼠的 NOX4 活性改善氧化应激和足细胞损伤


足细胞损伤与蛋白尿和糖尿病肾病（DN）的进展有关。 NADPH 氧化酶 4 (NOX4) 是肾脏中活性氧 (ROS) 的主要来源，足细胞中 NOX4 因高葡萄糖而上调。在本研究中，我们在糖尿病 db/db 小鼠和人类足细胞中研究了丹参多酚酸盐对 DN 的影响及其潜在机制。我们证实，丹参多酚酸盐的给药表现出与 NOX1/NOX4 抑制剂 GKT137831 治疗糖尿病小鼠相似的有益效果，如白蛋白尿减弱、足细胞丢失和系膜基质积累减少所反映。我们进一步观察到丹参多酚酸盐减弱了 Nox4 蛋白和基于 NOX4 的 NADPH 氧化酶活性的增加，并恢复了糖尿病肾脏中足细胞的损失。在人类足细胞中，NOX4 主要定位于线粒体，Sal B 治疗可阻断 HG 诱导的线粒体 NOX4 衍生的超氧化物生成，从而改善足细胞凋亡，这种情况可以通过 AMPK 敲低来消除。因此，我们的结果表明 Sal B 具有肾脏保护能力，部分是通过 AMPK 介导的 NOX4 表达控制。综上所述，我们的结果表明，丹参多酚酸盐可以通过调节 DN 中的 NOX4 活性来预防葡萄糖诱导的氧化性足细胞损伤，并对 DN 具有新的治疗潜力。