ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells

American Journal of Physiology. Renal Physiology
Yosuke NagaiRimei Nishimura

Abstract

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db/db mice demonstrated increased gene expression of transforming growth factor (TGF)-β and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db/db mice was elevated compared with control db/m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db/db mice. These observations indicate that ROCK2 is a key player...Continue Reading

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Citations

Jul 3, 2020·Biomedicines·Yusuke TakedaRimei Nishimura
Jun 18, 2020·International Journal of Molecular Sciences·Daiji KawanamiMakito Tanabe
Feb 11, 2021·Antioxidants·Daiji KawanamiMakito Tanabe
Apr 4, 2021·International Journal of Molecular Sciences·Asfia SoomroJoan C Krepinsky
May 4, 2021·Frontiers in Immunology·Rong TangXiangcheng Xiao
May 16, 2021·Acta Pharmacologica Sinica·Yuan-Yuan ChenSen Zhang
Jun 18, 2021·Small GTPases·Clara SteichenNicolas Bourmeyster
Aug 18, 2021·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Alexandra Zanin-Zhorov, Bruce R Blazar
Oct 7, 2021·Journal of the American Heart Association·Yuxin LiJames K Liao
Oct 20, 2021·Rheumatology·Fabian A Mendoza, Sergio A Jimenez

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Methods Mentioned

BETA
PCR
pulldown
Pull-Down
pull down
Assay
immunoprecipitation assay
nuclear translocation
immunoprecipitation

Clinical Trials Mentioned

NCT02688647
NCT02852967

Software Mentioned

MetaVue

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