title: Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.
abstract: The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.
authors.affiliation: 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 430030, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: 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 430030, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University; Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430071, China.
authors.forename: Cheng-Biao
authors.initials: CB
authors.lastname: Xue
authors.affiliation: The Central Hospital of Taian, Taian 271000, China.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Li
authors.affiliation: 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 430030, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Xing
authors.affiliation: 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 430030, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: He
authors.affiliation: Academy of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Feng-Chao
authors.initials: FC
authors.lastname: Jiang
authors.affiliation: 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 430030, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Lu
authors.affiliation: 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 430030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001665:Binding Sites; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015195:Drug Design; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015870:Gene Expression; D007113:Immunity, Innate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization / Q000187:drug effects; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D016019:Survival Analysis; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010879:Piperazines; D013844:Thiazoles; D023201:CD40 Ligand