ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells
ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells
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DOI：
10.1152/ajprenal.00596.2018
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Nishimura, Rimei
中科院分区：
文献类型：
--
作者：
Nagai, Yosuke;Matoba, Keiichiro;Nishimura, Rimei
小 GTP 酶 Rho 及其效应器 Rho 激酶 (ROCK) 参与糖尿病肾病的发病机制。 Rho 激酶有两种亚型：ROCK1 和 ROCK2。然而，目前尚不清楚哪个主要参与糖尿病肾小球硬化的进展和促纤维化介质的调节。从 2 型糖尿病 db/db 小鼠中分离的肾小球显示转化生长因子 (TGF)-β 及其下游促纤维化介质的基因表达增加。 ROCK 的化学抑制抑制了分离的肾小球和培养的肾小球系膜细胞中促纤维化介质的表达。对这一观察结果背后的机制的研究揭示了通过 JNK 和 Erk 的磷酸化激活 ROCK 功能以及通过肌动蛋白动力学进行 NF-kappa B 的核转位。针对 ROCK1 和 ROCK2 的 siRNA 敲低表明，ROCK2 而不是 ROCK1 控制着这种纤维化机制。进一步的体内实验表明，与对照db/m小鼠相比，db/db小鼠肾皮质中的ROCK2活性升高。重要的是，口服 ROCK2 抑制剂可减弱 db/db 小鼠的肾 ROCK2 活性、白蛋白尿和肾小球纤维化。这些观察结果表明，ROCK2 在糖尿病肾损伤的发展中发挥着关键作用。肾小球ROCK2可能是治疗糖尿病肾病的潜在治疗靶点。
The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db/db mice demonstrated increased gene expression of transforming growth factor (TGF)-beta and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-kappa B via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db/db mice was elevated compared with control db/m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db/db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.