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Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis

Lei Jiang1, Lingling Xu, Junhua Mao

  • 1Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

Journal of the American Society of Nephrology : JASN
|May 11, 2013
PubMed

Insights

Ras homolog enriched in brain (Rheb) signaling activates kidney fibroblasts and promotes kidney fibrosis. Inhibiting Rheb/mammalian target of rapamycin complex 1 (mTORC1) signaling with rapamycin can prevent or treat kidney fibrosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Nephrology

Background:

  • Ras homolog enriched in brain (Rheb) is a small GTPase that regulates cell growth and survival via mammalian target of rapamycin complex 1 (mTORC1) signaling.
  • The specific role of Rheb/mTORC1 signaling in kidney fibroblast activation and subsequent renal fibrosis is not well understood.

Purpose of the Study:

  • To investigate the involvement of Rheb/mTORC1 signaling in kidney fibroblast activation and the development of interstitial renal fibrosis.
  • To determine if targeting Rheb/mTORC1 signaling could serve as a therapeutic strategy for kidney fibrosis.

Main Methods:

  • Activation of Rheb/mTORC1 signaling was assessed in fibrotic kidney samples and TGFβ1-treated rat kidney interstitial fibroblasts (NRK-49F cells).
  • The effects of inhibiting Rheb/mTORC1 signaling using rapamycin or Rheb small interfering RNA on fibroblast activation were examined.
  • Transgenic mouse models with ectopic Rheb expression or fibroblast-specific Tsc1 deletion were utilized to study the in vivo role of Rheb/mTORC1 signaling in renal fibrosis.
  • The impact of rapamycin treatment on fibrosis development in these mouse models was evaluated.

Main Results:

  • Rheb/mTORC1 signaling was found to be activated in myofibroblasts from fibrotic kidneys and upon TGFβ1 treatment of kidney fibroblasts.
  • Inhibition of Rheb/mTORC1 signaling effectively blocked TGFβ1-induced fibroblast activation.
  • Ectopic Rheb expression in transgenic mice led to kidney fibroblast activation, increased mTORC1 signaling, and progressive interstitial renal fibrosis, which was ameliorated by rapamycin.
  • Fibroblast-specific deletion of Tsc1 resulted in activated mTORC1 signaling and renal fibrosis, both reversed by rapamycin treatment.

Conclusions:

  • Rheb/mTORC1 signaling plays a critical role in promoting kidney fibroblast activation.
  • This signaling pathway significantly contributes to the development of interstitial renal fibrosis.
  • Targeting Rheb/mTORC1 signaling represents a potential therapeutic avenue for treating progressive kidney diseases characterized by fibrosis.

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