BMP‐2 suppresses renal interstitial fibrosis by regulating epithelial–mesenchymal transition

Abstract

Dysregulation of epithelial-to-mesenchymal transition (EMT) may contribute to renal fibrogenesis. Our previous study indicated that bone morphogenetic protein-2 (BMP-2) significantly reversed transforming growth factor (TGF)-β1-induced renal interstitial fibrosis. In this study, we examined the underlying mechanism and elucidate the regulation of EMT process under BMP-2 treatment. Cultured renal interstitial fibroblast (NRK-49F) was treated with TGF-β1 (10 ng/ml) with or without BMP-2 (10-250 ng/ml) for 24 h. The expression of α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, or Snail transcriptional factors was analyzed by immunofluorescence staining or Western blotting. Cell migration was analyzed by wound-healing assay. NRK-49F treated with TGF-β1 induced significant EMT including upregulatioin of α-SMA, fibronectin, and snail proteins and down-regulation of E-cadherin. Interestingly, co-treatment with BMP-2 dose-dependently reversed TGF-β1-induced cellular fibrosis, cell migration, and above EMT change. The above effect was closely correlated with Snail since BMP-2 dose- and time-course dependently induced a significant decrease in the level of Snail. Moreover, Snail siRNA significantly reversed TGF-β1-induced increases in the level of α-SMA and fibronectin (intracellular and extracellular). We suppose that BMP-2 have the potential to attenuate TGF-β1-induced renal interstitial fibrosis by attenuating Snail expression and reversing EMT process.

TGF-beta1 increases cell rigidity by enhancing expression of smooth muscle actin: Keloid-derived fibroblasts as a model for cellular mechanics

“…Myocardin-related transcription factors A and B are key regulators of TGF-b1-induced fibroblast to myofibroblast differentiation in rat embryonic fibroblasts [38]. BMP-2 suppresses renal interstitial fibrosis by regulating SMA expression in renal interstitial fibroblasts [39]. In a repetitive TGF-beta-induced dermal fibrosis mouse model mimicking keloids, the dermal fibrosis and SMA expression is abrogated by inhibitor with dipeptidyl peptidase IV-like activity [40].…”

Gremlin Is a Downstream Profibrotic Mediator of Transforming Growth Factor-Beta in Cultured Renal Cells

“…A similar mechanism has been suggested to be involved in aristolochic acid-induced EMT [22]. BMP-7 and BMP-2 have proven to attenuate TGF-β 1 -induced renal interstitial fibrosis by reversing EMT process [23,24]. However, BMP-independent mechanisms may mediate Gremlin intracellular actions.…”

Molecular alterations that drive breast cancer metastasis to bone

“…15 Experimental evidence from murine mammary cancer 4T1 cells highlights the critical early role that TGF-b has in inducing EMT. Cells treated with TGF-b acquired a spindle-like morphology and expression of the mesenchymal markers N-cadherin and vimentin.…”