Renoprotective Role of Ketone Bodies in Adenine-Induced Kidney Injury in Mice

Background: Ketone bodies have long been recognized as a crucial energy source during fasting; however, recent years have seen increasing interest in their organ-protective properties. This study aimed to investigate the renoprotective effects of ketone bodies using a mouse model of adenine-induced nephropathy. Methods: To evaluate the effect of exogenous ketone body supplementation, 1,3-butanediol—a precursor of the ketone body, β-hydroxybutyrate (BHB)—was orally administered to mice with adenine-induced tubulointerstitial injury. To assess the role of systemic and renal ketogenesis, adenine nephropathy was induced in mice with liver- or proximal tubule-specific deletion of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis. Furthermore, to determine whether the renoprotective effect of 1,3-butanediol was mediated by increased ATP availability, proximal tubule-specific succinyl-CoA:3-ketoacid CoA transferase (SCOT) knockout mice were generated. SCOT is a key enzyme required for the utilization of ketone bodies as an energy source. Results: In the mouse adenine nephropathy model, oral administration of 1,3-butanediol prevented the elevation of plasma cystatin C levels and attenuated histological kidney damage. These effects were accompanied by a significant reduction in apoptosis, as assessed by TUNEL staining, and downregulation of genes associated with inflammation and fibrosis. In contrast, liver- and proximal tubule-specific HMGCS2 deficiency did not mitigate the elevation of plasma cystatin C levels. Furthermore, although 1,3-butanediol administration markedly increased renal HMGCS2 expression, its renoprotective effect was preserved in proximal tubule-specific HMGCS2-deficient mice. Conversely, proximal tubule-specific SCOT deficiency abolished the inhibitory effect of 1,3-butanediol on plasma cystatin C elevation in this model. Conclusion: Exogenous ketone body supplementation confers renoprotective effects via SCOT-mediated ketolysis in the mouse adenine nephropathy model. However, systemic or kidney-specific endogenous ketogenesis alone was insufficient to elicit renoprotection. These findings suggest that systemic ketone body administration is a promising therapeutic strategy for chronic kidney disease.