Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
Endocr J. 2023 Aug 28;70(8):771-776. doi: 10.1507/endocrj.EJ23-0282. Epub 2023 Jul 20.
Diabetic nephropathy is a public health problem worldwide. Our understanding of the molecular machinery, as well as the clinical therapies for diabetic nephropathy, has evolved dramatically in recent years. However, even with this progress, there are residual risks of kidney failure and cardiovascular events in patients with diabetes. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in response to various pathologic stimuli in the context of diabetes. The contribution of ROCK has been investigated in vivo using gene deletion rodent models and specific inhibitors, which are providing key insights into the pathologic function of ROCK in diabetic nephropathy. ROCK has two isoforms, ROCK1 and ROCK2. Both isoforms are expressed in the kidney, including mesangial cells, podocytes, and endothelial cells. ROCK1 blunts AMP-activated protein kinase (AMPK), while ROCK2 negatively regulates peroxisome proliferator-activated receptor α (PPARα) to inhibit fatty acid oxidation, both of which lead to structural and functional impairment of glomeruli in diabetes. Of note, ROCK signaling is activated in the kidney of animal models and patients with diabetes. In addition, an observational study has shown that fasudil hydrochloride, an ATP-competitive selective ROCK inhibitor, significantly attenuated proteinuria among patients with diabetes. These findings highlight the promising prospects for the development of a ROCK-centered approach against the progression of diabetic nephropathy.
糖尿病肾病是一个全球性的公共卫生问题。近年来，我们对糖尿病肾病的分子机制以及临床治疗方法的理解有了显著的进展。然而，即使有了这些进展，糖尿病患者仍然存在肾功能衰竭和心血管事件的残余风险。在糖尿病的背景下，Rho 相关卷曲螺旋蛋白激酶（ROCK）会对各种病理刺激作出反应而被激活。通过使用基因敲除啮齿动物模型和特定的抑制剂，已经在体内研究了 ROCK 的作用，这些研究为 ROCK 在糖尿病肾病中的病理作用提供了关键的见解。ROCK 有两种同工型，ROCK1 和 ROCK2。这两种同工型都在肾脏中表达，包括肾小球系膜细胞、足细胞和内皮细胞。ROCK1 抑制 AMP 激活的蛋白激酶（AMPK），而 ROCK2 负向调节过氧化物酶体增殖物激活受体α（PPARα）以抑制脂肪酸氧化，这两者都会导致糖尿病肾小球的结构和功能受损。值得注意的是，ROCK 信号在糖尿病动物模型和患者的肾脏中被激活。此外，一项观察性研究表明，ROCK 的选择性 ATP 竞争性抑制剂法舒地尔盐酸盐可显著减轻糖尿病患者的蛋白尿。这些发现强调了以 ROCK 为中心的方法在阻止糖尿病肾病进展方面具有广阔的前景。
