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 journalArticle

Abstract

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)
JournalCell death and differentiation
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Hepatocyte Growth Factor
PPAR gamma
Acute Kidney Injury
Cell Death
Fibroblasts
Kidney
Staurosporine
Apoptosis
Conditioned Culture Medium
Reperfusion Injury
Down-Regulation
Proto-Oncogene Proteins c-met
Fibroblast Growth Factors
Cultured Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury. / Gui, Yuan; Lu, Qingmiao; Gu, Mengru; Wang, Mingjie; Liang, Yan; Zhu, Xingwen; Xue, Xian; Sun, Xiaoli; He, Weichun; Yang, Junwei; Zhao, Allan Zijian; Xiao, Bo; Dai, Chunsun.

In: Cell death and differentiation, 01.01.2019.

Research output: Contribution to journalArticle

Gui, Y, Lu, Q, Gu, M, Wang, M, Liang, Y, Zhu, X, Xue, X, Sun, X, He, W, Yang, J, Zhao, AZ, Xiao, B & Dai, C 2019, 'Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury', Cell death and differentiation. https://doi.org/10.1038/s41418-019-0336-3
Gui, Yuan ; Lu, Qingmiao ; Gu, Mengru ; Wang, Mingjie ; Liang, Yan ; Zhu, Xingwen ; Xue, Xian ; Sun, Xiaoli ; He, Weichun ; Yang, Junwei ; Zhao, Allan Zijian ; Xiao, Bo ; Dai, Chunsun. / Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury. In: Cell death and differentiation. 2019.
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AU - Zhu, Xingwen

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AU - Sun, Xiaoli

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