Liu Feng, Zhang Siqi, Xu Ruisi, Gao Shuohui, Yin Jian
Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun, China.
Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China.
Kidney Blood Press Res. 2018;43(5):1425-1436. doi: 10.1159/000493380. Epub 2018 Sep 13.
BACKGROUND/AIMS: Endothelial-to-mesenchymal transition (EndMT) of glomerular endothelial cells (GEnCs) can induce albuminuria in diabetic nephropathy. Melatonin attenuates diabetic nephropathy, but its role and mechanism in EndMT of GEnCs in diabetic nephropathy remain unknown.
The effect of melatonin on EndMT induced by transforming growth factor (TGF)-β2 in human renal GEnCs was determined by assaying the expression of endothelial marker cells (VE-cadherin and CD31) and mesenchymal cells (α-SMA and Snail), as well as monolayer permeability. The molecular mechanism of melatonin in these processes was focused on miR-497/ROCK signaling. Furthermore, the effect and mechanism of melatonin in EndMT were confirmed in glomeruli of rats with streptozotocin-induced diabetes.
Melatonin increased expression of VE-cadherin and CD31 and inhibited α-SMA and Snail levels that were altered by TGF-β2 in GEnCs. Melatonin treatment reduced expression and activity of ROCK1 and ROCK2, which suppressed TGF-β2-induced hyperpermeability of GEnCs and EndMT of GEnCs. Melatonin reduced ROCK1 and ROCK2 expression and activity in TGF-β2-stimulated GEnCs by enhancing expression of miR-497, which targets ROCK1 and ROCK2. Furthermore, we found that melatonin inhibited EndMT in glomeruli and albuminuria in rats with streptozotocin-induced diabetes. MiR-497 expression increased, whereas ROCK1 and ROCK2 expression and activity decreased in melatonin-treated diabetic rats.
Melatonin attenuated EndMT of GEnCs via regulating miR-497/ROCK signaling in diabetic nephropathy. This study improves understanding of EndMT and the role of melatonin in diabetic nephropathy.
背景/目的：肾小球内皮细胞（GEnC）的内皮-间充质转化（EndMT）可诱发糖尿病肾病中的蛋白尿。褪黑素可减轻糖尿病肾病，但它在糖尿病肾病GEnC的EndMT中的作用及机制尚不清楚。
通过检测内皮标志物细胞（血管内皮钙黏蛋白和CD31）和间充质细胞（α-平滑肌肌动蛋白和Snail）的表达以及单层通透性，来确定褪黑素对人肾GEnC中转化生长因子（TGF）-β2诱导的EndMT的影响。褪黑素在这些过程中的分子机制聚焦于miR-497/ROCK信号通路。此外，在链脲佐菌素诱导的糖尿病大鼠肾小球中证实了褪黑素在EndMT中的作用及机制。
褪黑素增加了GEnC中血管内皮钙黏蛋白和CD31的表达，并抑制了TGF-β2改变的α-平滑肌肌动蛋白和Snail水平。褪黑素处理降低了ROCK1和ROCK2的表达及活性，抑制了TGF-β2诱导的GEnC高通透性和GEnC的EndMT。褪黑素通过增强靶向ROCK1和ROCK2的miR-497的表达，降低了TGF-β2刺激的GEnC中ROCK1和ROCK2的表达及活性。此外，我们发现褪黑素抑制了链脲佐菌素诱导的糖尿病大鼠肾小球中的EndMT和蛋白尿。在褪黑素处理的糖尿病大鼠中，miR-497表达增加，而ROCK1和ROCK2的表达及活性降低。
在糖尿病肾病中，褪黑素通过调节miR-497/ROCK信号通路减轻了GEnC的EndMT。本研究增进了对EndMT以及褪黑素在糖尿病肾病中作用的理解。
