Abstract: TH-PO0216
Multisubstrate Tracing Reveals Defective Lactate and Acetate Oxidation in Mouse Renal Cortex in Adenine-Induced Nephropathy
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
- Wilson, Rachel, Pfizer Inc, Cambridge, Massachusetts, United States
- Romoli, Simone, Pfizer Inc, Cambridge, Massachusetts, United States
- Jagarlapudi, Srinath, Pfizer Inc, Cambridge, Massachusetts, United States
- Swanson, Tyler, Pfizer Inc, Cambridge, Massachusetts, United States
- Granade, Mitchell, Pfizer Inc, Cambridge, Massachusetts, United States
- Pinkus, Cynthia, Pfizer Inc, Cambridge, Massachusetts, United States
- Crane, Justin, Pfizer Inc, Cambridge, Massachusetts, United States
Group or Team Name
- Internal Medicine Research Unit
Background
Chronic kidney disease (CKD) affects 10–15% of the population, with limited disease-modifying therapies. GWAS implicate proximal tubule epithelial cell (PTEC) dysfunction in CKD progression. PTECs have high energetic demands that are thought to be supported primarily by fatty acid oxidation, which has been shown to be impaired in CKD. However, the kidney uses additional energy substrates, and how their metabolism changes in CKD is poorly defined.
Methods
We developed a parallel substrate isotopic tracing method to profile renal non-canonical energy substrate metabolism in a mouse model of nephropathy induced by a 6-week 0.15% adenine diet. Ex vivo utilization (3H) and oxidation (14C) of radiolabeled substrates were measured in healthy kidney cortex, and in cortex and isolated tubules from adenine-fed mice. Renal function was assessed by measuring glomerular filtration rate (GFR).
Results
Adenine diet reduced GFR by 60% compared to control diet. In healthy cortex, 3H tracing showed robust utilization of lactate, acetate, and citrate, while 14C tracing revealed comparable oxidation of palmitate, lactate, and acetate with minimal citrate oxidation. Cortex from adenine-fed mice exhibited reduced utilization of lactate, acetate, citrate, and β-hydroxybutyrate, increased glucose utilization, and unchanged palmitate utilization. Consistently, adenine cortex showed reduced lactate and citrate oxidation, a trend toward reduced acetate oxidation, and preserved palmitate oxidation. Notably, tubules isolated from adenine kidneys showed increased palmitate and acetate oxidation, indicating compensatory metabolic adaptation in surviving nephrons.
Conclusion
Together, these data demonstrate substrate-selective impairment of renal metabolism in adenine-induced nephropathy, with preserved palmitate oxidation but reduced oxidation of non-canonical substrates. These findings indicate that renal metabolic remodeling depends on the disease model and demonstrate metabolic flexibility beyond fatty acid oxidation, supporting reports that tubular CPT1A deletion does not worsen kidney disease. Ongoing studies with the SGLT2 inhibitor dapagliflozin will test whether recovery of kidney function in adenine-induced nephropathy associates with restoration of lactate and acetate oxidation. Furthermore, improving PT lactate or acetate oxidation may provide a potential mechanism for treating CKD.
Funding
- Commercial Support – Pfizer Inc