HNF3α Targets Nckap1l and Promotes Renal Fibrosis Following Ischemia‐Reperfusion Injury

Abstract Chronic Kidney Disease (CKD) is a global health challenge, with acute kidney injury (AKI) from ischemia‐reperfusion injury (IRI) as a common cause. This study explored the role of Hepatocyte Nuclear Factor 3 alpha (HNF3α/FOXA1) in renal fibrosis and CKD after IRI. Kidney biopsy specimens from CKD patients and mouse models (IRI or unilateral ureteral obstruction) showed HNF3α upregulation in fibrotic kidneys, linked to renal function decline. Additional experiments demonstrated that deletion of HNF3α mitigated IRI‐induced renal fibrosis, and that overexpression of HNF3α led to increased fibrosis. Examination of the potential mechanism by transcriptome sequencing and CUT&Tag sequencing suggested that HNF3α promoted renal fibrosis by increasing the expression of the NCK associated protein 1 like (Nckap1l, formerly known as hematopoietic protein 1 [Hem1]), a vital component of the WAVE complex which plays a significant role in cytoskeletal regulation and cell migration. These results underscore the critical function of HNF3α in renal fibrosis following IRI, and also identify Nckap1l as a potential therapeutic target, thus opening new avenues for research and potential therapeutic interventions for CKD and renal fibrosis.