title: Secreted fibroblast-derived miR-34a induces tubular cell apoptosis in fibrotic kidney.
abstract: Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remains unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrate that miR-34a is markedly upregulated in tubulointerstitial spaces and microvesicles isolated from obstructed kidney. However, miR-34a is not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubation with TGF-β1. miR-34a is markedly upregulated in microvesicles isolated from the cell culture medium of TGF-β1-treated fibroblasts. These microvesicles act as a vector for delivery of upregulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induce the apoptosis of tubular cells. The exogenous miR-34a regulates tubular apoptosis by modulating the expression of the anti-apoptotic protein Bcl-2. Moreover, injection of exogenous miR-34a-containing microvesicles enhances tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructed kidney. This study reveals a new mechanism whereby microvesicle-mediated communication of miRNA between fibroblasts and tubular cells is involved in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis.
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Niu
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Su
authors.affiliation: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China daichunsun@njmu.edu.cn jwyang@njmu.edu.cn.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu 210003, China daichunsun@njmu.edu.cn jwyang@njmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D002460:Cell Line; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009395:Nephritis, Interstitial / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D053773:Transforming Growth Factor beta1
keywords: Apoptosis; Kidney fibrosis; Microvesicle; miR-34a; miRNA