Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD).Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia,the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood.Here,we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models.We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression.Sustained activation of HIF-1α,accompanied by the development of renal fibrotic lesions,was found in kidneys with severe AKI.The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor,5 mg·kg-1·d-1,i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days.Furthermore,we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5,which promoted progression of CKD following severe AKI.The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies.Moreover,we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1,which was the key factor governing HIF-1α-driven AKI to CKD progression.Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression.Thus,FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway.Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.