Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University; Minhang Branch, Zhongshan Hospital, Fudan University; Central Hospital of Minhang District, Shanghai, 201199, China.
Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Mol Cell Endocrinol. 2020 Apr 5;505:110730. doi: 10.1016/j.mce.2020.110730. Epub 2020 Jan 22.
Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions in diabetic nephropathy (DN) is unclear. We investigated the role of ANGPTL4 in the pathogenesis of DN. In DN rats, elevated ANGPTL4 expression was associated with increased proteinuria, glomerular hypertrophy, and ultrastructural changes in podocytes. In vitro, hyperglycemia induced the upregulation of ANGPTL4, which led to activation of integrin-β1/FAK signaling with increased apoptosis of podocytes and actin cytoskeleton derangement. These pathological changes were reversed by transfection with a lentivirus expressing short hairpin RNA against integrin-β1 or an ANGPTL4-neutralizing antibody in vitro. Furthermore, supplementation with the sialic acid precursor ManNAc reversed these pathological changes and conferred renoprotection in a mouse model of DN. Our findings suggest that ANGPTL4 mediates high glucose-induced loss of podocytes by modulating their detachment and apoptosis in vivo and in vitro. This study deepens our understanding of the mechanisms of podocyte loss in DN and shows targeting ANGPTL4-related signaling has therapeutic potential for DN.
血管生成素样蛋白 4（ANGPTL4）据报道可介导某些类型肾小球肾炎的蛋白尿。然而，糖尿病肾病（DN）病理条件下 ANGPTL4 对足细胞的影响的机制尚不清楚。我们研究了 ANGPTL4 在 DN 发病机制中的作用。在 DN 大鼠中，升高的 ANGPTL4 表达与蛋白尿增加、肾小球肥大和足细胞的超微结构变化有关。在体外，高血糖诱导 ANGPTL4 的上调，导致整合素-β1/FAK 信号的激活，增加足细胞的凋亡和肌动蛋白细胞骨架的紊乱。这些病理变化可以通过体外转染表达针对整合素-β1 的短发夹 RNA 的慢病毒或 ANGPTL4 中和抗体来逆转。此外，用唾液酸前体 ManNAc 补充可逆转这些病理变化，并在 DN 小鼠模型中提供肾脏保护作用。我们的研究结果表明，ANGPTL4 通过调节体内和体外足细胞的脱落和凋亡来介导高血糖诱导的足细胞丢失。这项研究加深了我们对 DN 中足细胞丢失机制的理解，并表明靶向 ANGPTL4 相关信号具有治疗 DN 的潜力。
