Tanshinone IIA mitigates peritoneal fibrosis by inhibiting EMT via regulation of TGF-β/smad pathway

Résumé

Purpose: To explore the effects of tanshinone IIA (T-IIA) on Dianeal-N PD-4 (PDF)-induced expression of fibrogenic cytokines in human peritoneal mesothelial cells (HPMCs), and to elucidate the mechanisms of action involved. Methods: Seven groups of HPMCs were used in the study: control group, PDF group, T-IIA group, LY364947 group, and 2 transforming growth factor-β (TGF-β) groups (TGF-β+ 50 μM T-IIA and TGF-β+ 100 μM T- IIA). The expression levels of mRNA and protein of TGF-β, smad2, smad7, α-smooth muscle actin(α-SMA), fibronectin, collagen І, E-cadherin, N-cadherin, matrix metalloprotein-2(MMP-2), and MMP-9 in the various groups were determined by reverse transcription-polymerase chain reaction (RTPCR) and Western blotting as appropriate. Results: The expressions of α-SMA, fibronectin, collagen І, TGF-β and smad2 were significantly upregulated in HPMCs by PDF treatment, but smad7 was down-regulated, relative to the control group (p < 0.01).These PDF-induced effects were reversed by T-IIA (p < 0.05). Inhibition of TGF-β/smad pathway by LY364947 treatment led to significant decrease in the expressions of fibrosis-related proteins, when compared with PDF group (p < 0.05). TGF-β treatment also produced numerous spindleshaped HPMCs characteristic of epithelial-mesenchymal transition (EMT). However, this morphological transition was alleviated, and the expression levels of EMT-related proteins were significantly downregulated by exposure to the two doses of T-IIA (p < 0.05). Conclusion: Tanshinone IIA inhibits EMT in HPMCs by regulating TGF-β/smad pathway, thus mitigating peritoneal fibrosis. Therefore, T-IIA has promising potential as a new drug for the treatment of peritoneal dialysis (PD)-induced fibrosis. Keywords: Peritoneal dialysis, Peritoneal fibrosis, Tanshinone IIA, Epithelial-mesenchymal transition

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