PRDM16 deficiency triggered by TGF-β signaling aggravated renal fibrosis by promoting tubular mitochondrial dysfunction

AbstractTGF-β signaling is the master modulator of renal fibrosis. However, its targeting drugs are failed to prevent the progression of chronic kidney disease (CKD) in clinical trials due to the extensive biological regulation of TGF-β signaling. It is necessary to investigate the precise downstream of TGF-β signaling that regulates renal fibrosis. In this study, we found that transcription factor PRDM16 expressed by human renal tubular epithelial cells was reduced markedly by TGF-β. Mechanistically, the activated Smad3 induced by TGF-β interacted with the cofactor, H-Ras, and bound to the promoter of PRDM16 to downregulate its transcription. Tubular-specific knockout of PRDM16 promoted renal fibrosis of unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (UIRI) mice by aggravating mitochondrial dysfunction.In vitro, PRDM16 blocked TGF-β-induced mitochondrial injury, and lipid deposition by upregulating PGC-1α. PRDM16 supplementary therapy preserved renal function and ameliorated the progression of renal fibrosis by protecting mitochondrial function. We report a novel downstream of TGF-β signaling, PRDM16 for attenuating renal fibrosis by protecting tubular mitochondrial function.