| First Author | Xue X | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 28 | Pages | 11119-11130 |
| PubMed ID | 29794026 | Mgi Jnum | J:267134 |
| Mgi Id | MGI:6197427 | Doi | 10.1074/jbc.RA118.002191 |
| Citation | Xue X, et al. (2018) Protein kinase Calpha drives fibroblast activation and kidney fibrosis by stimulating autophagic flux. J Biol Chem 293(28):11119-11130 |
| abstractText | Kidney fibrosis is a histological hallmark of chronic kidney disease and arises in large part through extracellular matrix deposition by activated fibroblasts. The signaling protein complex mTOR complex 2 (mTORC2) plays a critical role in fibroblast activation and kidney fibrosis. Protein kinase Calpha (PKCalpha) is one of the major sub-pathways of mTORC2, but its role in fibroblast activation and kidney fibrosis remains to be determined. Here, we found that transforming growth factor beta1 (TGFbeta1) activates PKCalpha signaling in cultured NRK-49F cells in a time-dependent manner. Blocking PKCalpha signaling with the chemical inhibitor Go6976 or by transfection with PKCalpha siRNA largely reduced expression of the autophagy-associated protein lysosomal-associated membrane protein 2 (LAMP2) and also inhibited autophagosome-lysosome fusion and autophagic flux in the cells. Similarly to chloroquine, Go6976 treatment and PKCalpha siRNA transfection also markedly inhibited TGFbeta1-induced fibroblast activation. In murine fibrotic kidneys with unilateral ureteral obstruction (UUO) nephropathy, PKCalpha signaling is activated in the interstitial myofibroblasts. Go6976 administration largely blocked autophagic flux in fibroblasts in the fibrotic kidneys and attenuated the UUO nephropathy. Together, our findings suggest that blocking PKCalpha activity may retard autophagic flux and thereby prevent fibroblast activation and kidney fibrosis. |
