Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease
Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease
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DOI：
10.1038/s41598-019-44194-3
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发表时间：
2019-05-22
影响因子：
4.6
通讯作者：
Lee, Eun Young
中科院分区：
文献类型：
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作者：
Kang, Jeong Suk;Lee, Seung Joo;Lee, Eun Young
MYH9是一种广泛表达的编码非肌肉肌球蛋白重链的基因，也在足细胞中表达，并与肾小球病理生理学相关。然而，与蛋白尿相关的MYH9相关肾小球疾病的潜在机制知之甚少。因此，我们研究MYH9在糖尿病肾损伤中的作用和机制。MYH9表达在糖尿病患者和动物的肾小球中以及在体外用Ang II处理的足细胞中降低。血管紧张素II治疗和siRNA介导的MYH9敲低足细胞导致肌动蛋白细胞骨架重组，细胞粘附减少，肌动蛋白相关蛋白下调，白蛋白通透性增加。Ang II处理增加了NOX 4的表达和ROS的产生。血管紧张素Ⅱ受体阻断剂氯沙坦和活性氧清除剂NAC恢复MYH9表达在血管紧张素Ⅱ处理的足细胞，减弱破坏肌动蛋白细胞骨架和降低白蛋白通透性。此外，MYH9在足细胞中的过表达恢复了Ang II对肌动蛋白细胞骨架和肌动蛋白相关蛋白的影响。Ang II介导的TRPC 6活化降低MYH9表达。这些结果表明，在糖尿病肾病中，Ang II介导的MYH9耗竭可能通过TRPC 6介导的Ca2+内流和NOX 4介导的ROS产生诱导结构和功能足细胞损伤来增加滤过屏障通透性。这些发现揭示了MYH9在维持尿过滤屏障完整性方面的新功能。MYH9可能是治疗糖尿病肾病的潜在靶点。
MYH9, a widely expressed gene encoding nonmuscle myosin heavy chain, is also expressed in podocytes and is associated with glomerular pathophysiology. However, the mechanisms underlying MYH9-related glomerular diseases associated with proteinuria are poorly understood. Therefore, we investigated the role and mechanism of MYH9 in diabetic kidney injury. MYH9 expression was decreased in glomeruli from diabetic patients and animals and in podocytes treated with Ang II in vitro. Ang II treatment and siRNA-mediated MYH9 knockdown in podocytes resulted in actin cytoskeleton reorganization, reduced cell adhesion, actin-associated protein downregulation, and increased albumin permeability. Ang II treatment increased NOX4 expression and ROS generation. The Ang II receptor blocker losartan and the ROS scavenger NAC restored MYH9 expression in Ang II-treated podocytes, attenuated disrupted actin cytoskeleton and decreased albumin permeability. Furthermore, MYH9 overexpression in podocytes restored the effects of Ang II on the actin cytoskeleton and actin-associated proteins. Ang II-mediated TRPC6 activation reduced MYH9 expression. These results suggest that Ang II-mediated MYH9 depletion in diabetic nephropathy may increase filtration barrier permeability by inducing structural and functional podocyte injury through TRPC6-mediated Ca2+ influx by NOX4-mediated ROS generation. These findings reveal a novel MYH9 function in maintaining urinary filtration barrier integrity. MYH9 may be a potential target for treating diabetic nephropathy.