Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury

Yuan Gui, Qingmiao Lu, Mengru Gu, Mingjie Wang, Yan Liang, Xingwen Zhu, Xian Xue, Xiaoli Sun, Weichun He, Junwei Yang, Allan Zijian Zhao, Bo Xiao, Chunsun Dai

Research output: Contribution to journalArticlepeer-review


Kidney fibroblasts play a crucial role in dictating tubular cell fate and the outcome of acute kidney injury (AKI). The underlying mechanisms remain to be determined. Here, we found that mTOR signaling was activated in fibroblasts from mouse kidneys with ischemia/reperfusion injury (IRI). Ablation of fibroblast Rheb or Rictor promoted, while ablation of fibroblast Tsc1 protected against tubular cell death and IRI in mice. In tubular cells cultured with conditioned media (CM) from Rheb−/− or Rictor−/− fibroblasts, less hepatocyte growth factor (HGF) receptor c-met signaling activation or staurosporine-induced cell apoptosis was observed. While CM from Tsc1−/− fibroblasts promoted tubular cell c-met signaling activation and inhibited staurosporine-induced cell apoptosis. In kidney fibroblasts, blocking mTOR signaling downregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and HGF. Downregulating fibroblast HGF expression or blocking tubular cell c-met signaling facilitated tubular cell apoptosis. Notably, renal PPARγ and HGF expression was less in mice with fibroblast Rheb or Rictor ablation, but more in mice with fibroblast Tsc1 ablation than their littermate controls, respectively. Together, these data suggest that mTOR signaling activation in kidney fibroblasts protects against tubular cell death and dictates the outcome of AKI through stimulating PPARγ and HGF expression.

Original languageEnglish (US)
Pages (from-to)2774-2789
Number of pages16
JournalCell death and differentiation
Issue number12
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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