Matoba Keiichiro, Takeda Yusuke, Nagai Yosuke, Kanazawa Yasushi, Kawanami Daiji, Yokota Tamotsu, Utsunomiya Kazunori, Nishimura Rimei
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Department of Endocrinology and Diabetes Mellitus, Fukuoka University School of Medicine, Fukuoka, Japan.
JMA J. 2020 Jul 15;3(3):154-163. doi: 10.31662/jmaj.2020-0014. Epub 2020 Jun 19.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is strongly associated with cardiovascular mortality. Given the pandemic of obesity and diabetes, the elucidation of the molecular underpinnings of DKD and establishment of effective therapy are urgently required. Studies over the past decade have identified the activated renin-angiotensin system (RAS) and hemodynamic changes as important therapeutic targets. However, given the residual risk observed in patients treated with RAS inhibitors and/or sodium glucose co-transporter 2 inhibitors, the involvement of other molecular machinery is likely, and the elucidation of such pathways represents fertile ground for the development of novel strategies. Rho-kinase (ROCK) is a serine/threonine kinase that is under the control of small GTPase protein Rho. Many fundamental cellular processes, including migration, proliferation, and survival are orchestrated by ROCK through a mechanism involving cytoskeletal reorganization. From a pathological standpoint, several analyses provide compelling evidence supporting the hypothesis that ROCK is an important regulator of DKD that is highly pertinent to cardiovascular disease. In cell-based studies, ROCK is activated in response to a diverse array of external stimuli associated with diabetes, and renal ROCK activity is elevated in the context of type 1 and 2 diabetes. Experimental studies have demonstrated the efficacy of pharmacological or genetic inhibition of ROCK in the prevention of diabetes-related histological and functional abnormalities in the kidney. Through a bird's eye view of ROCK in renal biology, the present review provides a conceptual framework that may be widely applicable to the pathological processes of multiple organs and illustrate novel therapeutic promise in diabetology.
糖尿病肾病（DKD）是终末期肾病的主要原因，与心血管疾病死亡率密切相关。鉴于肥胖和糖尿病的流行，迫切需要阐明DKD的分子基础并建立有效的治疗方法。过去十年的研究已确定激活的肾素-血管紧张素系统（RAS）和血流动力学变化是重要的治疗靶点。然而，鉴于在接受RAS抑制剂和/或钠-葡萄糖协同转运蛋白2抑制剂治疗的患者中观察到的残余风险，其他分子机制可能也参与其中，阐明这些途径为开发新策略提供了丰富的土壤。Rho激酶（ROCK）是一种丝氨酸/苏氨酸激酶，受小GTPase蛋白Rho的控制。许多基本的细胞过程，包括迁移、增殖和存活，都由ROCK通过涉及细胞骨架重组的机制精心调控。从病理学角度来看，多项分析提供了有力证据，支持ROCK是DKD的重要调节因子且与心血管疾病高度相关这一假说。在基于细胞的研究中，ROCK会响应与糖尿病相关的各种外部刺激而被激活，并且在1型和2型糖尿病的情况下，肾脏ROCK活性会升高。实验研究已经证明，对ROCK进行药理或基因抑制可有效预防糖尿病相关的肾脏组织学和功能异常。通过对ROCK在肾脏生物学中的全面审视，本综述提供了一个可能广泛适用于多个器官病理过程的概念框架，并阐述了糖尿病学中的新治疗前景。
