TNFSF14 deficiency attenuates the ischemia/reperfusion-induced acute kidney injury-to-chronic kidney disease transition by upregulating PGC-1α expression

Ischemia/reperfusion (IR) is one of the usual causes of acute kidney injury (AKI), and renal fibrosis is the major feature of IR-AKI progressing to chronic kidney disease (CKD). In this study, we established a bilateral IR-induced renal interstitial fibrosis mouse model, and found that TNFSF14 deficiency significantly ameliorated IR-AKI to CKD transition, as shown by reduced renal interstitial fibrosis and epithelial-mesenchymal transition (EMT) of renal proximal tubular cells (PTCs). Moreover, TNFSF14 signaling was associated with reduced peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression, along with changes in fatty acid oxidation (FAO)-related markers, accelerated mitochondrial injury and lipid accumulation during the IR-AKI to CKD transition. Mechanistically, TNFSF14 was invo lved in the suppression of PGC-1α expression and enhanced EMT by way of potentiating Twist1 expression in renal PTCs. Collectively, our results suggest that TNFSF14 pathway plays a critical role in the IR-AKI to CKD transition, and blocking the TNFSF14 pathway may be a potential therapeutic strategy to mitigate AKI progression to CKD.