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Kidney Week

Abstract: PO0604

The Role of HNF4α in CKD Progression

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Lynch, Emily Patricia, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Acquired kidney mitochondrial dysfunction is a prominent feature of Chronic Kidney Disease (CKD), and is associated with onset and progression of CKD. HNF4α is a transcription factor highly expressed in proximal tubules which controls the expression of genes involved in critical metabolic pathways. As a result, mutations in Hnf4α are associated with mitochondrial defects. We previously found that Hnf4α is reduced in the kidneys of Col4a3KO mice with progressive CKD and it correlates with hyperphosphatemia. Here we tested the hypothesis that kidney Hnf4α is reduced in response to hyperphosphatemia and that Hnf4α decline in CKD contributes to mitochondrial dysfunction and CKD progression.

Methods

We fed WT mice a control (Ctr) and a high phosphate diet (HPi) for 6 weeks. We confirmed that Hnf4α expression was reduced in the kidneys Col4a3KO mice by RT-PCR and next performed RNA sequencing (RNAseq) to identify genes and molecular pathways affected by HNF4α reduction in CKD. Finally, to further evaluate the causal role of Hnf4α reduction in CKD progression, we treated Col4a3KO mice with a daily dose of 30μg/g of HNF4α antagonist (BI-6015) for 5 days.

Results

WT mice fed a HPi diet showed a significant 70% reduction in kidney HNF4α mRNA and protein expression, suggesting that hyperphosphatemia, a hallmark of progressive CKD, contributes to HNF4α downregulation in the kidney. Kidney molecular profiling by RNAseq of Col4a3KO mice showed increased acquired mitochondrial dysfunction and reduced oxidative phosphorylation, suggesting that impaired mitochondrial function strongly contributes to CKD progression. Downstream pathway analyzes showed that the vast majority of these genes (~80 %) are regulated by HNF4α. Pharmacological inhibition or HNF4α in Col4a3KO mice led to an accelerated decline in kidney function (200% increase in BUN), demonstrating the crucial role of HNF4α in CKD progression.

Conclusion

These results suggest that HNF4α is a master regulator of mitochondrial function in kidney and might represent a novel therapeutic target to improve outcomes in CKD.

Funding

  • NIDDK Support