Abstract: FR-PO0364
Treatment of AKI by Activation of Branched-Chain Amino Acid (BCAA) Catabolism
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
- DiMartino, Samaneh, Stony Brook Medicine, Stony Brook, New York, United States
- Kwak, Soo Ah, Stony Brook Medicine, Stony Brook, New York, United States
- Piret, Sian E., Stony Brook Medicine, Stony Brook, New York, United States
Background
Acute kidney injury (AKI) particularly affects proximal tubule (PT) cells and is associated with profound metabolic dysfunction. We previously showed that BCAA (valine, leucine, and isoleucine) catabolic enzymes are downregulated in aristolochic acid I (AAI)-induced AKI, and that simultaneous pharmacologic activation of BCAA catabolism with BT2 attenuates AAI-induced AKI. In the current study, we tested whether delayed BT2 administration can treat AKI after injury has already been initiated.
Methods
Male C57BL/6 mice were treated with two doses of 3mg/kg AAI administered 72 hours apart, followed by euthanasia after a further 4 days, to induce PT–specific AKI. BT2 was administered daily, using two delayed-treatment strategies. In the first strategy, BT2 treatment was initiated after the second AAI injection (total of 4 injections). In the second strategy, BT2 was initiated 48 hours after the first AAI injection and continued for four additional days after the final AAI dose (total of 6 injections). Serum was collected for blood urea nitrogen and creatinine measurement, and kidneys were harvested for histology and immunofluorescence for PT brush borders (Lotus lectin) and PT injury (KRT-20).
Results
Initiating BT2 after the second AAI dose produced only modest protection, with a significant decrease in BUN and KRT-20 but not creatinine. In contrast, initiating BT2 48 hours after the first AAI injection and continuing treatment after the second AAI exposure resulted in broader improvement in AKI outcomes. BT2 attenuated kidney dysfunction and reduced KRT-20 expression. Consistent with reduced tubular injury, Lotus lectin staining was increased in both delayed-treatment strategies, suggesting partial preservation or restoration of PT brush-border integrity.
Conclusion
Pharmacologic activation of BCAA catabolism with BT2 attenuated AAI-induced AKI, supporting BCAA catabolic dysfunction as a modifiable contributor to PT injury. However, the degree of protection depended on treatment timing. BT2 was more effective when administered during early injury, whereas delayed treatment after injury establishment provided partial benefit. Thus, BCAA catabolic activation may be a promising metabolic strategy for AKI attenuation, but early intervention may be critical for maximal therapeutic efficacy.
Funding
- NIDDK Support