Lin Tang1, Hui Li2, Rong Gou2, Genyang Cheng2, Yuanyuan Guo2, Yudong Fang2, Fengmei Chen2. 1. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China. Electronic address: tanglin0627@gmail.com. 2. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Abstract
OBJECTIVE: The pathogenesis of interstitial fibrosis in diabetic nephropathy (DN) is an intractable problem without good therapy. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) is an important mechanism for tubular epithelial cells undergoing profibrotic change in DN. Endothelin-1 (ET-1) is an important cytokine which can cause fibrogenesis and is reportedly involved in DN. However, the role of ET-1 in EMT in DN is unknown. The present study was designed to investigate the role of ET-1 in high glucose-induced EMT and the signaling pathway mediating the effect of ET-1 in renal tubular cells. METHOD: Tubular epithelial cells (NRK52E) were treated with normal glucose (d-glucose 5.6mmol/L, NG), high glucose (30mmol/L, HG), high osmotic (d-glucose 5.6mmol/L+d-mannitol 24.4mmol/L), HG+ETA antagonist BQ123 (2μg/ml), ET-1, ET-1+ hypoxia inducible factor (HIF)-1α siRNA, CoCl2 (100μmol/L), CoCl2+HIF-1α siRNA or CoCl2+BQ123. The supernatant level of ET-1 was measured by ELISA and the expression of vimentin, E-cadherin and HIF-1α was detected by RT-PCR and western blot. RESULT: The ET-1 level increased markedly in the supernatant of NRK52E incubated with HG. In NRK52E induced with HG or ET-1, the expression of vimentin was upregulated, whereas the expression of E-cadherin was downregulated. BQ123 attenuated HG- and CoCl2-induced EMT while HIF-1α siRNA did not affect ET-1 induced EMT. CONCLUSIONS: High glucose induced ET-1 production that mediated the EMT induced by high glucose in renal tubular epithelial cells, and HIF-1α acted as the upstream signal to regulate ET-1.
OBJECTIVE: The pathogenesis of interstitial fibrosis in diabetic nephropathy (DN) is an intractable problem without good therapy. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) is an important mechanism for tubular epithelial cells undergoing profibrotic change in DN. Endothelin-1 (ET-1) is an important cytokine which can cause fibrogenesis and is reportedly involved in DN. However, the role of ET-1 in EMT in DN is unknown. The present study was designed to investigate the role of ET-1 in high glucose-induced EMT and the signaling pathway mediating the effect of ET-1 in renal tubular cells. METHOD: Tubular epithelial cells (NRK52E) were treated with normal glucose (d-glucose 5.6mmol/L, NG), high glucose (30mmol/L, HG), high osmotic (d-glucose 5.6mmol/L+d-mannitol 24.4mmol/L), HG+ETA antagonist BQ123 (2μg/ml), ET-1, ET-1+ hypoxia inducible factor (HIF)-1α siRNA, CoCl2 (100μmol/L), CoCl2+HIF-1α siRNA or CoCl2+BQ123. The supernatant level of ET-1 was measured by ELISA and the expression of vimentin, E-cadherin and HIF-1α was detected by RT-PCR and western blot. RESULT: The ET-1 level increased markedly in the supernatant of NRK52E incubated with HG. In NRK52E induced with HG or ET-1, the expression of vimentin was upregulated, whereas the expression of E-cadherin was downregulated. BQ123 attenuated HG- and CoCl2-induced EMT while HIF-1α siRNA did not affect ET-1 induced EMT. CONCLUSIONS: High glucose induced ET-1 production that mediated the EMT induced by high glucose in renal tubular epithelial cells, and HIF-1α acted as the upstream signal to regulate ET-1.
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