Physiological Role of Renal Ketogenesis

Background: The organ-protective effects of dietary restriction and SGLT2 inhibitors observed in large clinical trials have highlighted ketone bodies as potential mechanistic mediators. While the liver is the primary site of ketone body production, emerging evidence suggests that the kidney also possesses this capability. However, the physiological role of renal ketogenesis remains poorly understood. In this study, we investigated the functional significance of renal ketone body. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on kidney tissues from mice under both fasting and non-fasting conditions. Immunostaining for Hmgcs2, the rate-limiting enzyme in ketone body synthesis, was conducted to determine its localization. Proximal tubule-specific Hmgcs2 knockout mice (Hmgcs2-PTCKO) were generated by crossing SLC34a1-Cre mice with Hmgcs2 floxed mice. Wild-type (WT) and Hmgcs2-PTCKO mice were subjected to fasting. Renal tissue ketone levels were assessed using mass spectrometry imaging (MSI). Urine volume, osmolality, and electrolyte concentrations were also measured. Results: scRNA-seq revealed that Hmgcs2 expression was predominantly localized to the proximal tubules during fasting. Immunostaining confirmed this finding. In Hmgcs2-PTCKO mice, Hmgcs2 expression was markedly reduced in the proximal tubules. Although blood ketone levels were not significantly altered, renal tissue ketone concentrations during fasting were significantly decreased in Hmgcs2-PTCKO mice. These mice also exhibited increased urine volume and urinary sodium excretion compared to WT controls under fasting conditions. Conclusion: These findings suggest that ketone bodies are locally produced in the kidneys during fasting and contribute to the urine-concentrating mechanism. Impaired renal ketogenesis may result in a reduced urinary concentrating capacity during fasting.