Rapamycin inhibits epithelial-to-mesenchymal transition of peritoneal mesothelium cells through regulation of Rho GTPases.
Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a key process of peritoneal fibrosis. Rapamycin has been previously shown to inhibit EMT of PMCs and prevent peritoneal fibrosis. In this study, we investigated the undefined molecular mechanisms by which rapamycin inhibits EMT of PMCs. To define the protective effect of rapamycin, we initially used a rat PD model which was daily infused with 20 mL of 4.25% high glucose (HG) dialysis solution for 6 weeks to induce fibrosis. The HG rats showed decreased ultrafiltration volume and obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β1. Rapamycin significantly ameliorated those pathological changes. Next, we treated rat PMCs with HG to induce EMT and/or rapamycin for indicated time. Rapamycin significantly inhibited HG-induced EMT, which manifests as increased expression of α-SMA, fibronectin, and collagen I, decreased expression of E-cadherin, and increased mobility. HG increased the phosphorylation of PI3K, Akt, and mTOR. Importantly, rapamycin inhibits the RhoA, Rac1, and Cdc42 activated by HG. Moreover, rapamycin repaired the pattern of F-actin distribution induced by HG, reducing the formation of stress fiber, focal adhesion, lamellipodia, and filopodia. Thus, rapamycin shows an obvious protective effect on HG-induced EMT, by inhibiting the activation of Rho GTPases (RhoA, Rac1, and Cdc42).
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Shilong
S
Xiang
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Meng
M
Li
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xishao
X
Xie
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Zhoutao
Z
Xie
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Qin
Q
Zhou
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Yuanshi
Y
Tian
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Institute of Translational Medicine, Zhejiang University, Hangzhou, China.
Weiqiang
W
Lin
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xiaohui
X
Zhang
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Hong
H
Jiang
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Nephrology department, Zhejiang University International Hospital, Hangzhou, China.
Zhangfei
Z
Shou
Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Jianghua
J
Chen
D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005353:Fibronectins; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D006801:Humans; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage*; D020764:cdc42 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics
D005353:Fibronectins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D005947:Glucose; D020123:Sirolimus
Rho GTPases; epithelial-mesenchymal transition; high glucose; mesothelial cells; rapamycin