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Role for Rictor/mTORC2 Signaling in Mediating TGFb1‐induced Fibroblast Activation and Kidney Fibrosis
Author(s) -
dai chunsun
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.663.14
Subject(s) - mtorc2 , cancer research , kidney , pi3k/akt/mtor pathway , biology , mtorc1 , nephropathy , fibrosis , kidney disease , lupus nephritis , signal transduction , microbiology and biotechnology , endocrinology , medicine , diabetes mellitus , disease
The Mammalian target of rapamycin (mTOR) is recently identified with two structurally distinct multiprotein complexes. MTORC1 has been implicated in the pathogenesis of several types of kidney disease. The role and mechanisms for mTORC2 in TGFb1‐induced fibroblast activation and kidney brosis have not been reported. Here, we found that TGFβ1 could activate Rictor/mTORC2 signaling in cultured NRK‐49F cells, a rat kidney broblast cell line. Blocking Rictor/mTORC2 signaling with either Rictor or Akt1 small interfering RNA transfection markedly inhibited TGFβ1‐induced fibronection and a‐SMA expression. In addition, Western blotting or immuno‐staining results showed that Rictor/mTORC2 signaling was activated in kidney interstitial myobroblasts from mice with unilateral ureter obstruction (UUO) nephropathy and from patients with various types of kidney disease including diabetic nephropathy, IgA nephropathy, lupus nephritis as well as membranous nephropathy. To further investigate the role of Rictor/mTORC2 signaling in fibroblast activation and kidney fibrosis, a mouse model with fibroblast‐specific deletion of Rictor was generated with Cre/LoxP system. The knockouts were born normal and no obvious kidney dysfunction or kidney morphologic abnormality was found within 5 months after birth. However, kidney interstitial fibrosis and inflammatory cell infiltration were markedly diminished in the knockouts at 1 and 2 weeks after UUO compared to those in their control littermates. Together, these results suggest that Rictor/mTORC2 signaling activation mediates TGFb1‐induced broblast activation and contributes to the development of kidney brosis, possibly providing a therapeutic target for chronic kidney diseases.