Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease

被引：57

作者：

Kang, Jeong Suk ^{[1
,2
]}

Lee, Seung Joo ^{[1
]}

Lee, Ji-Hye ^{[3
]}

Kim, Ji-Hee ^{[4
]}

Son, Seung Seob ^{[1
]}

Cha, Seung-Kuy ^{[4
]}

Lee, Eun Soo ^{[5
]}

Chung, Choon Hee ^{[5
]}

Lee, Eun Young ^{[1
,2
]}

机构：

[1] Soonchunhyang Univ, Dept Internal Med, Cheonan Hosp, Cheonan, South Korea

[2] Soonchunhyang Univ, Coll Med, Inst Tissue Regenerat, Cheonan, South Korea

[3] Soonchunhyang Univ, Cheonan Hosp, Dept Pathol, Cheonan, South Korea

[4] Yonsei Univ, Wonju Coll Med, Dept Physiol, Wonju, South Korea

[5] Yonsei Univ, Wonju Coll Med, Dept Internal Med, Wonju, South Korea

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

新加坡国家研究基金会;

关键词：

NONMUSCLE MYOSIN IIA; GLOMERULAR PROTEIN; RENAL-DISEASE; EXPRESSION; MUTATIONS; ACTIN; GENE; TRPC6; ASSOCIATIONS; CYTOSKELETON;

D O I：

10.1038/s41598-019-44194-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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