Kidney Week

Abstract: FR-PO0381

Inhibition of Fatty Acid Metabolism Protects Against AKI

Session Information

• AKI: Mechanisms - Metabolism and Repair
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Hammoud, Safaa, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States

Safaa Hammoud, PhD

• Laha, Dipranjan, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States

Dipranjan Laha

• Kivan, Husam, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States

Husam Kivan, MD

• Gewin, Leslie S., Washington University in St Louis School of Medicine, St. Louis, Missouri, United States

Leslie S. Gewin, MD, FASN

Background

Acute kidney injury (AKI) is a major health problem targeting proximal tubules (PT) due to their high energy demand. The energetic needs are fueled by fatty acid oxidation (FAO), which can generate reactive oxygen species (ROS), part of AKI pathophysiology. Previous data showed that carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme for mitochondrial FAO, improved response to chronic kidney injury. However, the role of FAO and CPT1A in AKI is unclear.

Methods

Mice lacking tubular CPT1A (Cpt1a^CKO) were generated using Pax8-rTTA;tetO-Cre with recombination induced by doxycycline diet. Mice were injured by bilateral ischemia-reperfusion injury (biIRI, 23 min) and aristolochic acid (AA, 3.5 mg/kg). Pharmacological FAO inhibitor, ranolazine (305mg/kg), was used with C57BL/6 mice in biIRI. As peroxisomal FAO may compensate CPT1A loss, we generated mice lacking CPT1A and peroxisomal FAO rate limiting enzyme, ACOX1, (Cpt1a; Acox1^CKO) and injured with AA. We measured kidney function (BUN, creatinine), tubular injury (Lcn2 qPCR), cell death (TUNEL assay), and ROS (8-OHdG staining). Primary PT from Cpt1a^fl/fl mice treated with adenovirus Cre (Cpt1a^-/-) and injured with hypoxia (1%O2)/reperfusion (H/R) or AA and cell death was measured (cleaved caspase 3, annexin/PI). We investigated the role of pentose phosphate pathway (PPP) by measuring NADP/NADPH levels in kidneys and blocking PPP by glucose-6-phosphate dehydrogenase inhibitor in vitro using 6-aminonicotinamide (6AN).

Results

Both Cpt1a^CKO and ranolazine-treated mice were protected in AKI, shown by reduced BUN, creatinine, Lcn2 expression, and cell death. The protection was not due to peroxisomal FAO compensation as Cpt1a; Acox1^CKO mice were protected in AKI. Cpt1a^-/- PT and ranolazine-treated PT had reduced cell death after AA or H/R. Prior snRNAseq data showed increased expression of enzymes linked to PPP in Cpt1a^CKO kidneys. Consistent with this, Cpt1a^CKO uninjured kidneys had higher glutathione levels and biIRI-injured Cpt1a^CKO kidneys had significantly lower ROS and NADP:NADPH compared to Cpt1a^fl/fl. CPT1A deletion protective effect could be mediated through increased PPP activity augmenting glutathione and NADPH which reduces ROS. The mechanistic role of PPP was confirmed as 6AN abolished the protective effects of CPT1A deletion.

Conclusion

FAO inhibition, genetically or pharmacologically, protects against AKI through increased PPP activity and reduced ROS.

Funding

• NIDDK Support