Abstract
Hydrogen sulfide (H2S) has anti-fibrotic potential in lung, kidney and other organs. The exogenous H2S is released from sodium hydrosulfide (NaHS) and can influence the renal fibrosis by blocking the differentiation of quiescent renal fibroblasts to myofibroblasts. But whether H2S affects renal epithelial-to-mesenchymal transition (EMT) and the underlying mechanisms remain unknown. Our study is aimed at investigating the in vitro effects of H2S on transforming growth factor-β1 (TGF-β1)-induced EMT in renal tubular epithelial cells (HK-2 cells) and the associated mechanisms. The induced EMT is assessed by Western blotting analysis on the expressions of α-SMA, E-cadherin and fibronectin. HK-2 cells were treated with NaHS before incubating with TGF-β1 to investigate its effect on EMT and the related molecular mechanism. Results demonstrated that NaHS decreased the expression of α-SMA and fibronectin, and increased the expression of E-cadherin. NaHS reduced the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II). In addition, NaHS attenuated TGF-β1-induced increase of β-catenin expression and ERK phosphorylation. Moreover, it inhibited the TGF-β1-induced nuclear translocation of ββ-catenin. These effects of NaHS on fibronectin, E-cadherin and TβR I were abolished by the ERK inhibitor U0126 or β-catenin inhibitor XAV939, or β-catenin siRNA interference. We get the conclusion that NaHS attenuated TGF-β1-induced EMT in HK-2 cells through both ERK-dependent and β-catenin-dependent pathways.
Highlights
Hydrogen sulfide (H2S) is an endogenous gaseous physiological molecule, produced in mammalian tissues from L-cysteine mainly by two pyridoxal-5’-phosphate-dependent enzymes, cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT)[1–3]
Treatment with NaHS reduced the activation of the transforming growth factor-β1 (TGF-β1) signaling caused by ureteral obstruction (UO), suggesting an inverse relationship between the H2S level and the in kidney fibrosis [4], opening the possibility for H2S as a potential therapeutical target for kidney fibrosis, and our study aimed to investigate the mechanism of antifibrotic effect of H2S
We investigated the effect of NaHS on TGFβ1-induced epithelialto-mesenchymal transition (EMT) in human proximal tubular epithelial cells (HK-2 cells) and the underlying mechanisms related to ERK and Wnt/catenin pathways
Summary
Hydrogen sulfide (H2S) is an endogenous gaseous physiological molecule, produced in mammalian tissues from L-cysteine mainly by two pyridoxal-5’-phosphate-dependent enzymes, cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT)[1–3]. Hydrogen Sulfide Inhibits Transforming Growth Factor-β1-Induced EMT. K. Jung et al has shown that in ureteral obstruction (UO)-induced kidney fibrosis, the levels of CBS and CSE, and the H2S concentration are decreased in kidney, whereas sodium hydrosulfide (NaHS, a H2S producer) diminished the suppressing effect of UO on CBS, CSE and H2S. Treatment with NaHS reduced the activation of the transforming growth factor-β1 (TGF-β1) signaling caused by UO, suggesting an inverse relationship between the H2S level and the in kidney fibrosis [4], opening the possibility for H2S as a potential therapeutical target for kidney fibrosis, and our study aimed to investigate the mechanism of antifibrotic effect of H2S. The role of TGF-β signaling in kidney fibrosis is attributed to its ability to induce epithelialto-mesenchymal transition (EMT)[5]. The abnormal induction of EMT in kidney has been shown to contribute to tubulointerstitial fibrosis, the final common path to renal fibrosis [7]
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