Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Department of Pathology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Commun Biol. 2022 Apr 8;5(1):341. doi: 10.1038/s42003-022-03300-4.
Loss of podocytes is a common feature of diabetic renal injury and a key contributor to the development of albuminuria. We found that podocyte Rho associated coiled-coil containing protein kinase 2 (ROCK2) is activated in rodent models and patients with diabetes. Mice that lacked ROCK2 only in podocytes (PR2KO) were resistant to albuminuria, glomerular fibrosis, and podocyte loss in multiple animal models of diabetes (i.e., streptozotocin injection, db/db, and high-fat diet feeding). RNA-sequencing of ROCK2-null podocytes provided initial evidence suggesting ROCK2 as a regulator of cellular metabolism. In particular, ROCK2 serves as a suppressor of peroxisome proliferator-activated receptors α (PPARα), which rewires cellular programs to negatively control the transcription of genes involved in fatty acid oxidation and consequently induce podocyte apoptosis. These data establish ROCK2 as a nodal regulator of podocyte energy homeostasis and suggest this signaling pathway as a promising target for the treatment of diabetic podocytopathy.
足细胞丢失是糖尿病肾损伤的一个常见特征，也是导致蛋白尿发生的关键因素。我们发现，糖尿病啮齿动物模型和患者的足细胞中 Rho 相关卷曲螺旋蛋白激酶 2（ROCK2）被激活。在多种糖尿病动物模型（即链脲佐菌素注射、db/db 和高脂肪饮食喂养）中，仅在足细胞中缺乏 ROCK2 的小鼠（PR2KO）对蛋白尿、肾小球纤维化和足细胞丢失具有抗性。对 ROCK2 敲除的足细胞进行 RNA 测序提供了初步证据，表明 ROCK2 是细胞代谢的调节剂。具体而言，ROCK2 作为过氧化物酶体增殖物激活受体 α（PPARα）的抑制剂，重新调整细胞程序以负调控参与脂肪酸氧化的基因的转录，从而诱导足细胞凋亡。这些数据确立了 ROCK2 作为足细胞能量稳态的节点调节剂，并表明该信号通路是治疗糖尿病性足细胞病的有希望的靶点。
