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

Area of Science:

• Nephrology
• Molecular Biology
• Pathology

Background:

• Chronic Kidney Disease (CKD) is a significant global health issue.
• Acute Kidney Injury (AKI) due to ischemia-reperfusion injury (IRI) is a major contributor to CKD.
• Renal fibrosis is a common pathway leading to CKD progression.

Purpose of the Study:

• To investigate the role of Hepatocyte Nuclear Factor 3 alpha (HNF3α/FOXA1) in renal fibrosis following IRI.
• To elucidate the underlying molecular mechanisms by which HNF3α influences kidney fibrosis.
• To identify potential therapeutic targets for mitigating renal fibrosis and CKD.

Main Methods:

• Analysis of kidney biopsy specimens from CKD patients and IRI/unilateral ureteral obstruction mouse models.
• Gene expression analysis using transcriptome sequencing.
• Chromatin accessibility profiling using CUT&Tag sequencing.
• Functional studies involving gene deletion and overexpression of HNF3α.

Main Results:

• HNF3α was upregulated in fibrotic kidneys and correlated with declining renal function.
• HNF3α deletion attenuated IRI-induced renal fibrosis, while its overexpression exacerbated fibrosis.
• HNF3α promotes renal fibrosis by upregulating NCK associated protein 1 like (Nckap1l), a component of the WAVE complex involved in cytoskeletal regulation.

Conclusions:

• HNF3α plays a critical role in promoting renal fibrosis after IRI.
• Nckap1l is identified as a downstream target of HNF3α in the context of renal fibrosis.
• Targeting HNF3α or Nckap1l presents potential therapeutic strategies for CKD and renal fibrosis.