title: M2 macrophage polarization modulates epithelial-mesenchymal transition in cisplatin-induced tubulointerstitial fibrosis.
abstract: Cisplatin-induced nephrotoxicity leaded to apoptosis of tubular epithelial cells (ECs) and tubulointerstitial fibrosis through ROS stress and inflammatory cytokines. Tubulointerstitial fibrosis caused by cisplatin might be via activation of resident fibroblasts and epithelial-mesenchymal transition (EMT) of tubular ECs. Inflammatory niche was crucial for progression of fibroblast activation or EMT. It had been reported that M1/M2 macrophage polarization regulated pro-inflammation or pro-resolving phase in damage repairing. However, the role of macrophage polarization on cisplatin-induced EMT of tubular ECs had not been well elucidated. In this study, we used co-cultured cell model and condition medium to examine the interaction between tubular ECs, fibroblasts and M1/M2 macrophages. Our data showed that cisplatin alone induced incomplete EMT of tubular ECs, whereas fibroblasts co-cultured with cisplatin-treated ECs could lead to fibroblast activation by detection of α-SMA and collagen-1. Moreover, decrease of iNOS and increase of argenase-1 and CD206 expression indicated that macrophages co-cultured with cisplatin-treated ECs would turn to M2 phenotype. Finally, we found that condition medium of M2 macrophages could promote complete EMT of cisplatin-treated ECs. Taken together, cisplatin created an inflammatory niche via tubular ECs to activate fibroblasts and stimulated M2 macrophage polarization. M2 macrophages could turn back to promote EMT of cisplatin-treated ECs. These results revealed the cooperative roles of tubular ECs, fibroblast and M2 macrophages to facilitate the progression of renal fibroblasis.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, 100, Taipei, Taiwan.|National Taiwan University College of Medicine, 100, Taipei, Taiwan.
authors.forename: Chia-Cherng
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Life Science, National Taiwan Normal University, 106, Taipei, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chien
authors.affiliation: Metabolomic Research Center, China Medical University Hospital, 404, Taichung, Taiwan. ctching9@gmail.com.|Graduate Institute of Clinical Medical Science, China Medical University, 404, Taichung, Taiwan. ctching9@gmail.com.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Chang
keywords: Cisplatin; Epithelial-Mesenchymal Transition; M1/M2 macrophage polarization; Renal tubulointerstitial fibrosis