Protein kinase Cα drives fibroblast activation and kidney fibrosis by stimulating autophagic flux.

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 Cα 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 β1 (TGFβ1) activates signaling in cultured NRK-49F cells in a time-dependent manner. Blocking duanyu1531α signaling with the chemical inhibitor Go6976 or by transfection with duanyu1531α 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 duanyu1531α siRNA transfection also markedly inhibited TGFβ1-induced fibroblast activation. In murine fibrotic kidneys with unilateral ureteral obstruction (UUO) nephropathy, duanyu1531α 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 duanyu1531α activity may retard autophagic flux and thereby prevent fibroblast activation and kidney fibrosis.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}