title: Rapamycin ameliorates kidney fibrosis by inhibiting the activation of mTOR signaling in interstitial macrophages and myofibroblasts.
abstract: Interstitial fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Emerging data indicate that rapamycin can ameliorate kidney fibrosis by reducing the interstitial infiltrates and accumulation of extra cellular matrix (ECM). However, the cellular mechanism that regulates those changes has not been well understood yet. In this study, we revealed the persistent activation of mammalian target of rapamycin (mTOR) signaling in the interstitial macrophages and myofibroblasts, but rarely in injured proximal epithelial cells, CD4+ T cells, neutrophils, or endothelial cells, during the development of kidney fibrosis. Administration of rapamycin to unilateral ureteral obstruction (UUO) mice significantly suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-β(1). Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts.
authors.affiliation: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China. chenguochun@hotmail.com
authors.forename: Guochun
authors.initials: G
authors.lastname: Chen
authors.forename: Huihui
authors.initials: H
authors.lastname: Chen
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Youming
authors.initials: Y
authors.lastname: Peng
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Fuyou
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007422:Intestines / Q000166:cytology / Q000276:immunology; D007674:Kidney Diseases / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000494:pharmacology; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D007166:Immunosuppressive Agents; D009153:Mutagens; D053773:Transforming Growth Factor beta1; C000228:aristolochic acid I; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus