Fumarate-induced succination of A-kinase anchor protein 12 exacerbates renal inflammation and fibrosis.

Abstract

The inflammatory response resulting from the abnormal accumulation of metabolites has been implicated in the pathogenesis of organ fibrosis; however, its role and underlying mechanisms in renal fibrosis remain unclear. In this study, we observed a negative correlation between fumarate hydratase (FH) expression and the degree of renal fibrosis. Loss of FH function was associated with heightened inflammation and exacerbated tubulointerstitial damage in the kidney. Moreover, FH deficiency aggravated fibrosis in both the liver and lungs. Mechanistically, the depletion of FH in renal tubular cells led to fumarate accumulation. Fumarate directly succinated A-kinase anchoring protein 12 at cysteine 670, thereby diminishing its capacity to inhibit the activity of protein kinase Cζ (PKCζ). This process exacerbated renal inflammation and fibrosis by activating the downstream PKCζ/NF-κB and PKCζ/β-catenin pathways. Additionally, the upregulation of FH through adeno-associated virus 2/9-mediated FH overexpression markedly mitigated renal inflammation and fibrosis. These findings highlighted the important role of fumarate accumulation in the advancement of renal fibrosis, supporting FH as a potential therapeutic target in renal fibrosis.