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.
Highlights
Rho GTPase and its downstream effector Rho-kinase (Rho-associated, coiled-coil-containing protein kinase, ROCK) play important roles in the pathogenesis of systemic vascular diseases [1] by sensitizing the contractile machinery to Ca2+ [2,3], and negatively regulating NO production [4,5] in the vascular system
There is a vast literature showing an increase in relative kidney size in diabetic nephropathy in humans and rodent diabetic models
In line with Gojo’s study [13], the expression analysis of subunits or members of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the renal cortex demonstrated that the normalization of up-regulated NOX4, but not other subunits/members may contribute to the amelioration in nephropathy development in diabetic rats treated with fasudil
Summary
Rho GTPase and its downstream effector Rho-kinase (Rho-associated, coiled-coil-containing protein kinase, ROCK) play important roles in the pathogenesis of systemic vascular diseases [1] by sensitizing the contractile machinery to Ca2+ [2,3], and negatively regulating NO production [4,5] in the vascular system. The Rho/Rho-kinase pathway has been implicated in diabetes, including erectile dysfunction, cardiomyopathy, retinopathy, cerebro-vascular disease and nephropathy [6,7,8,9,10]. Diabetes mellitus is characterized by systemic endothelial dysfunction [12], which is the initial and key element for the development of nephropathy. Rho kinase may play an important role in renal fibrosis by enhancing signaling pathways involving transforming growth factor-beta, angiotensin II and nuclear factor-κB [15,16]. A growing body of evidence suggests the protective role of Rho kinase inhibitors in diabetes-induced vascular (aorta) dysfunction which can be due to inhibition of eNOS activity thereby less endothelial. We determined the contribution of Rho kinase to intrarenal artery endothelial dysfunction using an STZ-induced diabetes model and investigated the possible mechanisms
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