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RGC-32 Mediates Transforming Growth Factor-β-induced Epithelial-Mesenchymal Transition in Human Renal Proximal Tubular Cells*S⃞

By Wen-Yan Huang, Zu-Guo Li, Horea Rus, Xiaoyan Wang, Pedro A. Jose and Shi-You Chen


Epithelial-mesenchymal transition (EMT) occurs in several disease states, including renal fibrosis and carcinogenesis. Myofibroblasts produced from EMT of renal tubular cells are responsible for the deposition of extracellular matrix components in a large portion of renal interstitial fibrosis. Transforming growth factor-β (TGF-β) plays an essential role in the EMT of renal tubular cells, but the molecular mechanism governing this process remains largely unknown. In this study, we found that RGC-32 (response gene to complement 32) is critical for TGF-β-induced EMT of human renal proximal tubular cells (HPTCs). RGC-32 is not normally expressed in the HPTCs. However, TGF-β stimulation markedly activates RGC-32 while inducing an EMT, as shown by the induction of smooth muscle α-actin (α-SMA) and extracellular matrix proteins collagen I and fibronectin, as well as the reduction of epithelial marker E-cadherin. TGF-β function is mediated by several signaling pathways, but RGC-32 expression in HPTCs appears to be mainly regulated by Smad. Functionally, RGC-32 appears to mediate TGF-β-induced EMT of HPTCs. Blockage of RGC-32 using short hairpin interfering RNA significantly inhibits TGF-β induction of myofibroblast marker gene α-SMA while repressing the expression of E-cadherin. In contrast, overexpression of RGC-32 induces α-SMA expression while restoring E-cadherin. RGC-32 also inhibits the expression of another adherens junction protein, N-cadherin, suggesting that RGC-32 alone induces the phenotypic conversion of renal epithelial cells to myofibroblasts. Additional studies show that RGC-32 stimulates the production of extracellular matrix components fibronectin and collagen I. Mechanistically, RGC-32 induces EMT via the activation of other transcription factors such as Snail and Slug. RGC-32 knockdown inhibits the expression of Snail and Slug during TGF-β-induced EMT. Taken together, our data demonstrate for the first time that RGC-32 plays a critical role in TGF-β-induced EMT of renal tubular cells

Topics: Molecular Basis of Cell and Developmental Biology
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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