Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon 97239-2940, USA.
Curr Opin Nephrol Hypertens. 2011 Jan;20(1):77-83. doi: 10.1097/MNH.0b013e32834131f8.
The Rho GTPases and their downstream effectors Rho-associated kinases (ROCKs) appear to be the molecules that converge numerous pathophysiological signals triggered by the diabetic milieu and represent promising molecular targets for nephroprotective treatment in diabetes. The review discusses recent studies exploring the consequences of diabetes-induced Rho-ROCK activation in the kidney and the effects of ROCK inhibition (ROCKi) in experimental diabetic nephropathy.
Recent studies in models of type 1 and type 2 diabetes have indicated blood-pressure-independent nephroprotective actions of ROCKi in diabetic nephropathy. The underlying mechanisms include attenuation of diabetes-induced increases in renal expression of prosclerotic cytokines and extracellular matrix, resulting in slower development of glomerulosclerosis and interstitial fibrosis. The studies have also shown antiproteinuric affects of ROCKi that could be related to reductions in permeability of glomerular barrier and beneficial effects on podocytes. Moreover hemodynamic mechanisms might be also involved.
Despite remaining questions in this field, such as the specificity of currently available ROCKi, or the roles of individual ROCK isoforms, recent evidence in experimental diabetes, together with evidence generated in models of nondiabetic kidney disease and in clinical studies in patients with various cardiovascular disorders, suggest that ROCKi might in future broaden the spectrum of treatments available for patients with diabetic nephropathy.
Rho GTPases 及其下游效应物 Rho 相关激酶（ROCK）似乎是汇聚糖尿病环境引发的多种病理生理信号的分子，是糖尿病肾病治疗中具有前景的分子靶点。本文讨论了最近的研究，这些研究探讨了糖尿病诱导的 Rho-ROCK 激活在肾脏中的后果，以及 ROCK 抑制（ROCKi）在实验性糖尿病肾病中的作用。
1 型和 2 型糖尿病模型的最近研究表明，ROCKi 在糖尿病肾病中有血压-independent 的肾脏保护作用。潜在的机制包括抑制糖尿病诱导的促纤维化细胞因子和细胞外基质在肾脏中的表达增加，从而减缓肾小球硬化和间质纤维化的发展。这些研究还表明 ROCKi 具有抗蛋白尿作用，这可能与肾小球屏障通透性降低以及足细胞的有益作用有关。此外，血流动力学机制也可能参与其中。
尽管在该领域仍存在一些问题，例如目前可用的 ROCKi 的特异性，或个别 ROCK 同工型的作用，但最近在实验性糖尿病中获得的证据，以及在非糖尿病性肾脏疾病模型和各种心血管疾病患者的临床研究中获得的证据，表明 ROCKi 可能在未来拓宽糖尿病肾病患者的治疗选择范围。
