Abstract: TH-PO0220
Tubular PCK1 Defines a Stage-Dependent HNF4A Metabolic Program During Acute and Chronic Kidney Injury
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Hou, Yanjuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Hu, Xuemei, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Li, Chenyu, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background
Metabolic reprogramming is a hallmark of renal tubular injury, yet whether metabolic enzymes act merely as downstream consequences or function as upstream drivers of disease-associated transcriptional programs remains unresolved. Phosphoenolpyruvate carboxykinase 1 (PCK1) is a proximal tubule–enriched metabolic enzyme that is consistently downregulated in kidney injury, but its causal role and mechanistic link to transcriptional regulation are unknown.
Methods
We integrated epigenomic and transcriptomic analyses of human kidney data to identify PCK1 as a tubular trait gene and generated inducible tubule-specific Pck1 knockout mice. Mice were subjected to adenine-induced chronic kidney disease (CKD) and cisplatin-induced acute kidney injury (AKI). Transcriptomic profiling and integration with HNF4A ChIP-seq datasets were performed to define PCK1-associated transcriptional programs.
Results
PCK1 was identified as a proximal tubule–enriched trait gene positively associated with kidney function. Tubule-specific deletion of Pck1 markedly attenuated adenine-induced CKD, with improved renal function, reduced fibrosis, and suppression of inflammatory gene expression. Transcriptomic profiling revealed activation of HNF4A-associated metabolic pathways, including fatty acid oxidation and mitochondrial programs, along with enrichment of tubular differentiation and repair gene signatures. Integration with HNF4A ChIP-seq data demonstrated enrichment of differentially expressed genes at HNF4A binding sites, supporting activation of an HNF4A-driven transcriptional program. In contrast, Pck1 deletion exacerbated cisplatin-induced AKI, with worsened tubular injury, increased cell death, and suppression of differentiation markers. Notably, and in direct contrast to CKD, HNF4A-associated metabolic programs were suppressed in Pck1-deficient kidneys during acute injury, suggesting context-dependent regulation of HNF4A activity by PCK1.
Conclusion
These findings reveal a stage-dependent metabolism-to-transcription axis in which PCK1 regulates HNF4A activity to determine tubular cell fate under stress. While PCK1 loss enables adaptive metabolic reprogramming in chronic injury, it disrupts metabolic resilience in the acute setting. Targeting this axis may offer new opportunities to promote tubular recovery and slow CKD progression.