Abstract: TH-PO1159
Renoprotective Role of Ketone Bodies in Adenine-Induced Kidney Injury in Mice
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Omachi, Shoji, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Sugahara, Sho, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Kuwagata, Shogo, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Tanaka, Yuki, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Yamahara, Kosuke, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Yamahara, Mako, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Kanasaki, Masami, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
- Kume, Shinji, Shiga Ika Daigaku, Otsu, Shiga Prefecture, Japan
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.