Kidney Week

Abstract: PO2501

Reduction of Hnf4α Expression in CKD Accelerates Disease Progression

Session Information

• CKD: Metabolism, Epigenetics, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  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

Marta Martinez-Calle, PhD

• Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Guillaume Courbon,

• Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Xueyan Wang,

• Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Bridget Hunt-Tobey,

• Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Aline Martin,

• David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Valentin David,

Background

Renal mitochondrial dysfunction is a common feature of Chronic Kidney Disease (CKD) and is associated with cardiovascular disease. HNF4α is highly expressed in proximal tubules and controls the expression of genes involved in various metabolic pathways. Mutations in Hnf4α are associated with mitochondrial defects. We tested the hypotheses that renal Hnf4α decline in CKD contributes to mitochondrial dysfunction, CKD progression and onset of cardiovascular outcomes and that Hnf4α reduction in CKD is result of hyperphosphatemia.

Methods

We confirmed Hnf4α expression was reduced in the kidneys Col4a3^KO mice, model of progressive CKD. Next, we performed RNA sequencing (RNAseq) on kidneys collected from WT and Col4a3^KO mice to identify genes and molecular pathways altered by HNF4α reduction in CKD. We treated mice with a continuous administration of HNF4α antagonist (BI-6015, 3µg/g/day) for 8 weeks to study the effects of HNF4α suppression on renal and cardiac functions. To further evaluate the role of HNF4α reduction in CKD progression, we injected 30μg/g BI-6015 to Col4a3^KO mice for 5 days. We also generated WT and Col4a3^KO mice with a Hnf4α deletion in kidney proximal tubules (Hnf4α^Pax8cKO and Col4a3^KO/Hnf4α^Pax8cKO). Finally, to demonstrate that hyperphosphatemia reduces Hnf4a expression in the kidney, we fed WT mice a control and a high phosphate diet (HPi) for 6 weeks.

Results

RNAseq of Col4a3^KO mice kidneys showed impaired molecular pathways regulated by HNF4α, including increased mitochondrial dysfunction and reduced oxidative phosphorylation. Inhibition of HNF4α in WT mice led to kidney interstitial fibrosis and left ventricular hypertrophy, while in Col4a3^KO mice a shorter administration of HNF4α antagonist accelerated the decline in kidney function (+450% serum creatinine vs. Col4a3^KO-Ctr mice), demonstrating the crucial role of HNF4α in CKD progression. Similarly, Hnf4α deletion in proximal tubules impaired kidney function in WT mice and further worsened it in CKD animals. WT mice fed a HPi diet showed a 70% reduction in renal Hnf4α expression, suggesting that hyperphosphatemia contributes to renal HNF4α suppression.

Conclusion

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

Funding

• Other NIH Support