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

## TL;DR

This study shows that HNF3α promotes kidney fibrosis after injury and identifies Nckap1l as a potential target for treating chronic kidney disease.

## Contribution

The study identifies HNF3α and Nckap1l as key players in renal fibrosis and suggests them as potential therapeutic targets.

## Key findings

- HNF3α is upregulated in fibrotic kidneys and linked to worsened renal function.
- Deleting HNF3α reduces fibrosis, while overexpressing it increases fibrosis.
- HNF3α promotes fibrosis by upregulating Nckap1l, a component of the WAVE complex.

## 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.

Hepatocyte Nuclear Factor 3 alpha (HNF3α) is significantly upregulated in renal tubular epithelial cells of CKD patients and fibrotic mice. Deletion of HNF3α mitigates IRI‐induced renal fibrosis, while overexpression worsens it. HNF3α directly regulates NCK‐associated protein 1‐like (Nckap1l), whose overexpression exacerbates fibrosis. These findings suggest that the HNF3α/Nckap1l axis is a potential therapeutic target for CKD and renal fibrosis.