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Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis

Jianzhong Li1, Jiafa Ren1, Xin Liu1

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

Kidney International
|May 14, 2015
PubMed

Insights

Rictor/mTORC2 signaling drives kidney fibrosis by activating fibroblasts. Blocking this pathway reduces fibrosis in mouse models, suggesting it as a potential therapeutic target for chronic kidney diseases.

Area of Science:

  • Cell biology
  • Molecular biology
  • Nephrology

Background:

  • The mammalian target of rapamycin (mTOR) exists in two complexes, mTORC1 and mTORC2.
  • Rictor/mTORC2 protects against acute kidney injury.
  • The role of Rictor/mTORC2 in transforming growth factor-beta 1 (TGFβ1)-induced kidney fibrosis is unknown.

Purpose of the Study:

  • To investigate the role and mechanisms of Rictor/mTORC2 in TGFβ1-induced fibroblast activation and kidney fibrosis.
  • To determine if Rictor/mTORC2 signaling is activated in kidney fibrosis models.

Main Methods:

  • Treated NRK-49F cells with TGFβ1 to assess Rictor/mTORC2 activation.
  • Used small interfering RNAs (siRNAs) to block Rictor/mTORC2 signaling and analyzed fibronectin and α-smooth muscle actin expression.
  • Examined Rictor/mTORC2 activation in kidney interstitial myofibroblasts from mice with unilateral ureteral obstruction (UUO).
  • Generated and analyzed fibroblast-specific Rictor knockout mice in a UUO model.

Main Results:

  • TGFβ1 activated Rictor/mTORC2 signaling in cultured cells.
  • Blocking Rictor/mTORC2 with siRNAs inhibited TGFβ1-induced fibronectin and α-smooth muscle actin expression.
  • Rictor/mTORC2 signaling was activated in myofibroblasts during UUO.
  • Fibroblast-specific Rictor knockout mice showed reduced extracellular matrix deposition and inflammation after UUO compared to controls.

Conclusions:

  • Rictor/mTORC2 signaling activation mediates TGFβ1-induced fibroblast activation.
  • Rictor/mTORC2 signaling contributes to the development of kidney fibrosis.
  • Rictor/mTORC2 represents a potential therapeutic target for chronic kidney diseases.

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