title: Targeting of Rho kinase ameliorates impairment of diabetic endothelial function in intrarenal artery.
abstract: Endothelial dysfunction in kidney vasculature is the initial and key element for nephropathy in diabetes mellitus. Accumulating evidence suggests the protective role of Rho kinase inhibitors in endothelial dysfunction via modulating eNOS activity and NO production. However, the role of Rho kinase in diabetes-related endothelial dysfunction in kidney vasculature and the relevant mechanisms remain unknown. We assessed whether pharmacological inhibition of Rho kinase attenuates endothelial dysfunction in intrarenal arteries from type 1 diabetic rats. Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney. Fasudil treatment showed no improvement in diabetes-related abnormality in metabolic indices, but it significantly ameliorated endothelial dysfunction in intrarenal arteries and lessened the mesangial matrix expansion in the kidney cortex. Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor. In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.
authors.affiliation: Laboratory Center for Medical Science, Hangzhou Normal University, Hangzhou 310036, China. liucuiqing@hznu.edu.cn.
authors.forename: Hongping
authors.initials: H
authors.lastname: Yin
authors.forename: Hailong
authors.initials: H
authors.lastname: Ru
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Kang
authors.forename: Guohua
authors.initials: G
authors.lastname: Lin
authors.forename: Chuanfei
authors.initials: C
authors.lastname: Liu
authors.forename: Lixian
authors.initials: L
authors.lastname: Sun
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D013481:Superoxides; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D054460:rho-Associated Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1