Jian-Hua Liu1, Long He2, Zhi-Miao Zou3, Zuo-Chuan Ding3, Xue Zhang4, Hao Wang2, Ping Zhou3, Lin Xie3, Shuai Xing5, Cheng-Zhi Yi2. 1. Department of Surgery, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China17707230000@163.com. 2. Department of Surgery, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China. 4. Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China. 5. Department of Gastroenterology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Abstract
BACKGROUND/AIMS: The TLR/MyD88/NF-κB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRI). METHODS: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-β1 to induce EMT, and the cells were pretreated with TJ-M2010-2. RESULTS: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGF-β1, α-SMA, vimentin, MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-β1-induced EMT was blocked by TJ-M2010-2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited α-SMA expression. In addition, compared to the TGF-β1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IκBα. CONCLUSION: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF.
BACKGROUND/AIMS: The TLR/MyD88/NF-κB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRI). METHODS: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-β1 to induce EMT, and the cells were pretreated with TJ-M2010-2. RESULTS: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGF-β1, α-SMA, vimentin, MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-β1-induced EMT was blocked by TJ-M2010-2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited α-SMA expression. In addition, compared to the TGF-β1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IκBα. CONCLUSION: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF.
Authors: Gertrude J Nieuwenhuijs-Moeke; Søren E Pischke; Stefan P Berger; Jan Stephan F Sanders; Robert A Pol; Michel M R F Struys; Rutger J Ploeg; Henri G D Leuvenink Journal: J Clin Med Date: 2020-01-17 Impact factor: 4.241