Laboratory Center for Medical Science, Hangzhou Normal University, Hangzhou 310036, China.
Int J Mol Sci. 2013 Oct 14;14(10):20282-98. doi: 10.3390/ijms141020282.
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.
肾脏血管内皮功能障碍是糖尿病肾病的初始和关键因素。越来越多的证据表明，Rho 激酶抑制剂通过调节 eNOS 活性和 NO 产生在内皮功能障碍中具有保护作用。然而，Rho 激酶在糖尿病相关的肾脏血管内皮功能障碍中的作用及其相关机制尚不清楚。我们评估了 Rho 激酶抑制剂是否能减轻 1 型糖尿病大鼠肾内动脉的内皮功能障碍。Rho 激酶抑制剂法舒地尔有效降低了 MYPT1 的磷酸化水平，而不影响 ROCKs 在肾脏中的表达。法舒地尔治疗并没有改善与糖尿病相关的代谢指标异常，但它显著改善了肾内动脉的内皮功能障碍，并减轻了肾脏皮质中的系膜基质扩张。在机制上，Rho 激酶抑制剂还阻止了肾内动脉中超氧化物的产生和 NADPH 氧化酶中 NOX4 成员，这些都有助于糖尿病肾病的发生。总之，本研究结果表明，Rho 激酶通过增强氧化应激参与 1 型糖尿病的内皮功能障碍，并为 Rho 激酶抑制剂作为治疗糖尿病肾病的潜在治疗剂提供了新的证据。
