Abstract: FR-PO377

Targeting mTORC2/PKCα Inhibits Fibroblast Activation and Kidney Fibrosis Involving Blockade of Autophagic Flux

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Ren, Jiafa, Nanjing medical university, Nanjing, JIangSu, China
  • Dai, Chunsun, Nanjing medical university, Nanjing, JIangSu, China

Our published study reported that mTORC2 plays a critical role in fibroblast activation and kidney fibrosis. However, the role and mechanisms for PKCα, one of the major downstream targets of mTORC2, in regulating fibroblast activation and kidney fibrosis remain to be determined.


Rat kidney interstitial fibroblasts (NRK-49F) were stimulated with TGFβ1 and kidney fibrosis was induced by unilateral ureter obstruction (UUO) in CD1 mice. Go6976, a synthetic compound which selectively inhibits PKCα signaling, was employed.


Here, we found that TGFβ1 could activate PKCα in cultured NRK-49F cells with a time-dependent manner. Blocking PKCα signaling with either Go6976 or PKCα small interfering RNA could markedly inhibit TGFβ1-induced fibroblast activation. Additionally, Go6976 treatment could impair autophagic flux exhibited as decreased autophagosome-lysosome fusion and autophagic degradation accompanied by increased SQSTM1/p62 and LC3-II in NRK-49F cells. Similarly, 3-Methyladenine (3-MA) and Chloroquine (CQ), two classical authophagy inhibitors, could markedly suppress TGFβ1-induced fibroblast activation. In UUO kidneys, PKCα signaling was activated in the interstitial myofibroblasts and blocking PKCα with Go6976 could significantly ameliorate kidney fibrosis as well as inflammatory infiltration in the UUO kidneys compared to those treated with vehicle. Administration of Go6976 in mice could induce the accumulation of SQSTM1/p62 and LC3-II in the UUO kidneys, suggesting the blockade of autophagic flux in the fibrotic kidneys.


Together, these results suggest that blockade of PKCα attenuates TGFβ1-induced fibroblast activation may be through inhibiting autophagic flux. Targeting PKCα may provide a novel therapeutic strategy for patients with kidney fibrosis.


  • Government Support - Non-U.S.