Lian Mawi
Research Mentor(s): Abdulsalam Soofi
Mentor Department: Nephrology
Authors:
Session: Session 1 (9:00am – 9:50am)
Presentation Type: Poster 75
Abstract
Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease and need for renal replacement therapies. Metabolic dysregulation plays a pivotal role in the pathogenesis of DKD. Recent research has highlighted the link between ketone body, beta-hydroxybutyrate (BHB), and kidney function in humans; and the reno-protective effect in animal models, and a potential pathway through which SGLT2 inhibitors are effective. However, how BHB exerts its renoprotectiveeffects is unknown and the focus of this work. Methods: We collected the plasma, urine, and kidney from 24 weeks old diabetic db/db mice and control db/+mice. BHB was measured by LC-MS based targeted metabolomics. To determine whether further increase in BHB would impact DKD, db/db mice were fed with 5% 1,3-Butanediol (v/v in drinking water; 1,3-BD), which is a precursor of BHB and DKD metrics including albuminuria were measured. We quantified post-translational beta-hydroxybutyrylation (BHBylation) of proteins in db/db vs. db/+ mice. In HK-2 cell, mitochondrial function and BHB’s effect on fuel contribution in TCA cycle were tested by LC/MS based metabolic flux analysis (MFA). Results: We found that BHB level is significantly higher in plasma, urine, and kidney cortex in diabetic mice. 1,3-BD feeding markedly reduced urinary albumin level in 1,3 BD treated diabetic mice. We found that diabetic mice have significantly higher BHBylated lysine levels compared to non-diabetic controls. In HK-2 cells, MFA revealed BHBwas the preferred fuel source compared with glucose and palmitate. Conclusion: To summarize, BHB and BHBylated protein levels were higher in diabetic condition, and supplementation with the 1,3-Butanediol, led to lower urinary albumin excretion consistent with improved DKD. Increased in BHBylation associated with this protection suggests key role of this posttranslational modification in mediating improved metabolic rewiring in DKD and associated renoprotection
