Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Biochem Biophys Res Commun. 2023 Mar 15;649:32-38. doi: 10.1016/j.bbrc.2023.01.088. Epub 2023 Jan 31.
The small GTPase Rho and its effector Rho-kinase (ROCK) are activated in the diabetic kidney, and recent studies decade have demonstrated that ROCK signaling is an integral pathway in the progression of diabetic kidney disease. We previously identified the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism in diabetic glomeruli. However, the effect of pharmacological intervention for ROCK1 is not clear. In the present study, we show that the inhibition of ROCK1 by Y-27632 and fasudil restores fatty acid oxidation in the glomeruli. Mechanistically, these compounds optimize fatty acid utilization and redox balance in mesangial cells via AMPK phosphorylation and the subsequent induction of PGC-1α. A further in vivo study showed that the inhibition of ROCK1 suppressed the downregulation of the fatty acid oxidation-related gene expression in glomeruli and mitochondrial fragmentation in the mesangial cells of db/db mice. These observations indicate that ROCK1 could be a promising therapeutic target for diabetic kidney disease through a mechanism that improves glomerular fatty acid metabolism.
小 GTP 酶 Rho 及其效应物 Rho 激酶（ROCK）在糖尿病肾脏中被激活，最近的研究表明，ROCK 信号通路是糖尿病肾病进展的一个重要途径。我们之前已经确定了 ROCK1（ROCK 的一种同工型）在糖尿病肾小球中脂肪酸代谢中的独特作用。然而，ROCK1 的药理学干预效果尚不清楚。在本研究中，我们表明，用 Y-27632 和法舒地尔抑制 ROCK1 可恢复肾小球中的脂肪酸氧化。从机制上讲，这些化合物通过 AMPK 磷酸化和随后诱导 PGC-1α，优化了系膜细胞中脂肪酸的利用和氧化还原平衡。进一步的体内研究表明，抑制 ROCK1 可抑制 db/db 小鼠肾小球中与脂肪酸氧化相关的基因表达下调和系膜细胞中线粒体碎片化。这些观察结果表明，通过改善肾小球脂肪酸代谢的机制，ROCK1 可能成为治疗糖尿病肾病的有前途的治疗靶点。
