SAT-593 Assessing The Impact Of Varying Bcaa Intake And Catabolic Capacity On The Severity Of Diabetic Kidney Disease In Male Zsf1 Rats.

Abstract Disclosure: R. Lombard: None. M. Martín Taboada: None. Y. Al-Khafaji: None. M. Wallace: None. N. Docherty: None. Objective/Hypothesis Type 2 diabetes (T2D) is the leading cause of end-stage kidney disease (ESKD), with insulin resistance (IR) being a primary driver of chronic kidney disease (CKD) progression. Elevated levels of branched-chain amino acids (BCAAs) in IR are linked to worsened metabolic stress, potentially accelerating renal injury in CKD and increased dietary BCAA has been shown to increase insulin resistance in rodent models. This study investigates whether altered BCAA intake or metabolism contributes to IR-related CKD using the ZSF1 rat model of T2D and CKD. Methods: Twenty-nine male ZSF1 obese rats were used to assess the effects of 1. elevated dietary BCAA intake and 2. BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) treatment (a BCKDK inhibitor) on kidney injury. At 20 weeks, rats were stratified by baseline renal injury (urinary protein-to-creatinine ratio - uPCR) scores into five diet groups: control AA, control AA + BT2, high BCAA, high BCAA + BT2, and standard chow. This dietary intervention ran for 6 week (22-28 weeks of age). Kidney injury was reassessed via uPCR, and rats were humanely euthanised for fasting plasma and tissue collection. Data and Results Despite there being a trend towards decreased food intake among the high BCAA groups (+/- BT2), the diets had no significant impact on body weight, indicating a uniform physiological response to the experimental conditions, irrespective of diet composition or BT2 treatment. uPCR analysis showed significant differences: BT2 treatment reduced uPCR in both control and high BCAA diets, suggesting renoprotection. In contrast, the control AA diet and high BCAA diet without BT2 led to the highest uPCR scores, indicating increased kidney injury. Western blot analysis showed that BT2 reduced p-BCKDH in both diet groups and decreased BCKDK in high BCAA-fed rats, indicating enhanced BCAA catabolism via BCKDH activation. Conclusion: BT2 significantly improved uPCR, indicating potential as a therapy for kidney injury. These findings highlight the value of dietary and pharmacological interventions in managing CKD and metabolic dysfunction, supporting further clinical investigation. Funding disclosure This research was supported by the European Foundation for the Study of Diabetes (EFSD)/Boehringer Ingelheim - European Research Programme on “Multi-System Challenges in Diabetes”. Presentation: Saturday, July 12, 2025