title: Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis.
abstract: The mammalian target of rapamycin (mTOR) was recently identified in two structurally distinct multiprotein complexes: mTORC1 and mTORC2. Previously, we found that Rictor/mTORC2 protects against cisplatin-induced acute kidney injury, but the role and mechanisms for Rictor/mTORC2 in TGFβ1-induced fibroblast activation and kidney fibrosis remains unknown. To study this, we initially treated NRK-49F cells with TGFβ1 and found that TGFβ1 could activate Rictor/mTORC2 signaling in cultured cells. Blocking Rictor/mTORC2 signaling with Rictor or Akt1 small interfering RNAs markedly inhibited TGFβ1-induced fibronection and α-smooth muscle actin expression. Ensuing western blotting or immunostaining results showed that Rictor/mTORC2 signaling was activated in kidney interstitial myofibroblasts from mice with unilateral ureteral obstruction. Next, a mouse model with fibroblast-specific deletion of Rictor was generated. These knockout mice were normal at birth and had no obvious kidney dysfunction or kidney morphological abnormality within 2 months of birth. Compared with control littermates, the kidneys of Rictor knockout mice developed less interstitial extracellular matrix deposition and inflammatory cell infiltration at 1 or 2 weeks after ureteral obstruction. Thus our study suggests that Rictor/mTORC2 signaling activation mediates TGFβ1-induced fibroblast activation and contributes to the development of kidney fibrosis. This may provide a therapeutic target for chronic kidney diseases.
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jiafa
authors.initials: J
authors.lastname: Ren
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D000199:Actins; D002352:Carrier Proteins; D005353:Fibronectins; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; C508960:TGFB1 protein, human; C525637:rictor protein, mouse; C550254:rictor protein, rat; C498862:Acta2 protein, rat