Podocytes have foot processes that comprise an important cellular layer of the glomerular barrier involved in regulating glomerular permeability. The disturbance of podocyte function plays a central role in the development of proteinuria in diabetic nephropathy. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes, and these channels are involved in disturbing the glomerular filtration barrier in diabetes. Metformin is an anti-diabetic drug widely used for treating patients with type 2 diabetes. Recent studies have suggested that the therapeutic effect of metformin might be mediated by AMPK. The precise function of metformin on cellular function and intracellular signaling in podocytes under diabetic conditions is not fully understood. In this study, we demonstrated that metformin normalized TRPC6 expression via AMPKα1 activation in podocytes exposed to high glucose concentrations. A quantitative analysis showed that metformin increased the colocalization of TRPC6 and AMPKα1 subunits from 42% to 61% in standard glucose (SG) medium and from 29% to 52% in high glucose (HG) medium. AMPK activation was also necessary for maintaining appropriate levels of Rho-family small GTPase activity in HG conditions. Moreover, metformin through AMPK activation remodeled cytoskeleton dynamics, and consequently, reduced filtration barrier permeability in diabetic conditions.

中文翻译：

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二甲双胍可通过AMPK激活降低TRPC6的表达，并调节糖尿病条件下足细胞中的细胞骨架动力学。

足细胞的足突包括参与调节肾小球通透性的肾小球屏障的重要细胞层。足细胞功能的紊乱在糖尿病性肾病中蛋白尿的发展中起着核心作用。AMP激活的蛋白激酶（AMPK）是葡萄糖和脂肪酸代谢的关键调节剂，在肥胖和2型糖尿病中起主要作用。越来越多的证据表明，TRPC6通道是足细胞中钙转运的关键介质，并且这些通道与扰乱糖尿病患者的肾小球滤过屏障有关。二甲双胍是一种抗糖尿病药，广泛用于治疗2型糖尿病患者。最近的研究表明，二甲双胍的治疗作用可能是由AMPK介导的。在糖尿病条件下，二甲双胍对足细胞中细胞功能和细胞内信号转导的确切功能尚不完全清楚。在这项研究中，我们证明了二甲双胍通过暴露于高葡萄糖浓度的足细胞中的AMPKα1激活使TRPC6表达正常化。定量分析表明，二甲双胍将TRPC6和AMPKα1亚基的共定位作用在标准葡萄糖（SG）培养基中从42％增加到61％，在高葡萄糖（HG）培养基中从29％增加到52％。AMPK激活对于在HG条件下维持适当水平的Rho家族小GTPase活性也是必要的。此外，二甲双胍通过AMPK激活重塑了细胞骨架动力学，因此降低了糖尿病条件下的滤过屏障通透性。