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: Hongping Yin, Hailong Ru, Liping Yu, Yanhua Kang, Guohua Lin, Chuanfei Liu, Lixian Sun, Liyun Shi, Qinghua Sun, Cuiqing Liu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 14 Issue 10 Pg. 20282-98 (Oct 14 2013) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 24129169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Superoxides
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, rat
• rho-Associated Kinases
• Ppp1r12a protein, rat
• Protein Phosphatase 1

Topics

• Animals
• Arteries (drug effects, metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Diabetes Mellitus, Type 1 (metabolism)
• Diabetic Nephropathies (metabolism)
• Endothelial Cells (drug effects, metabolism)
• Kidney Cortex (drug effects, metabolism)
• Male
• NADPH Oxidase 4
• NADPH Oxidases (metabolism)
• Oxidative Stress (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Phosphatase 1 (metabolism)
• Rats
• Rats, Sprague-Dawley
• Superoxides (metabolism)
• rho-Associated Kinases (metabolism)