Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease
- Abstract
- 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 Ca(2+) 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.
- All Author(s)
- J. S. Kang
; S. J. Lee
; J. H. Lee
; J. H. Kim
; S. S. Son
; S. K. Cha
; E. S. Lee
; C. H. Chung
; E. Y. Lee
- Issued Date
- 2019
- Type
- Article
- Keyword
- Acetylcysteine/pharmacology
Actin Cytoskeleton/drug effects/ultrastructure
Angiotensin II/pharmacology/*physiology
Animals
Calcium/metabolism
Cell Adhesion
Cell Line, Transformed
Diabetes Mellitus, Experimental/metabolism/pathology; Diabetic Nephropathies/metabolism/*pathology; Down-Regulation; Humans; Losartan/pharmacology; Mice; Mice, Inbred C57BL; Microfilament Proteins/metabolism; Molecular Motor Proteins/biosynthesis/genetics/*physiology; Myosin Heavy Chains/biosynthesis/genetics/*physiology; NADPH Oxidase 4/biosynthesis/genetics; Podocytes/drug effects/*metabolism/ultrastructure; RNA Interference; Rats; Rats, Inbred Strains; Reactive Oxygen Species/metabolism; Receptors, Leptin/deficiency; TRPC6 Cation Channel/physiology
- ISSN
- 2045-2322
- Citation Title
- Scientific Reports
- Citation Volume
- 9
- Citation Number
- 1
- Citation Start Page
- 7679
- Citation End Page
- 7679
- Language(ISO)
- eng
- DOI
- 10.1038/s41598-019-44194-3
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/909
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