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

Jeong Suk Kang, Seung Joo Lee, Ji Hye Lee, Ji Hee Kim, Seung Seob Son, Seungkuy Cha, Eun Soo Lee, Choon Hee Chung, Eun Young Lee

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Article number7679
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

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Podocytes
Diabetic Nephropathies
Angiotensin II
Down-Regulation
Wounds and Injuries
Actin Cytoskeleton
Permeability
Actins
Albumins
Losartan
Myosin Heavy Chains
Proteinuria
Cell Adhesion
Small Interfering RNA
Proteins
Kidney
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Kang, Jeong Suk ; Lee, Seung Joo ; Lee, Ji Hye ; Kim, Ji Hee ; Son, Seung Seob ; Cha, Seungkuy ; Lee, Eun Soo ; Chung, Choon Hee ; Lee, Eun Young. / Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease. / Kang, Jeong Suk; Lee, Seung Joo; Lee, Ji Hye; Kim, Ji Hee; Son, Seung Seob; Cha, Seungkuy; Lee, Eun Soo; Chung, Choon Hee; Lee, Eun Young.

In: Scientific reports, Vol. 9, No. 1, 7679, 01.12.2019.

Research output: Contribution to journalArticle

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