J Am Soc Nephrol. 2026 Jan 21. doi: 10.1681/ASN.0000001014. Online ahead of print.

ABSTRACT

BACKGROUND: Abnormal renal fatty acid oxidation in kidney disease suggests that dysregulated metabolism is a key component of kidney disease pathogenesis. While the liver is the main ketogenic organ, the rate-limiting enzyme for ketogenesis, mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), is induced in the proximal tubule of the kidney during fasting. We previously demonstrated that HMGCS2 induced in the kidney does not contribute to the circulating pool of ketones during fasting and cannot compensate for hepatic ketogenic deficiency. We hypothesized that kidney HMGCS2 may be acting locally within the kidney to maintain normal function during metabolic stress or injury.

METHODS: Mice with kidney or liver specific deletion of Hmgcs2 were subjected to ischemia/reperfusion injury (IRI). Kidney histology, metabolomics and lipidomics were analyzed. Mice were placed on a ketogenic diet for four days to increase plasma and kidney ketone content. Using novel mouse models with proximal tubular hemagglutinin-tagged mitochondria with or without Hmgcs2 deletion, proximal tubular-specific mitochondria were isolated and fatty acid oxidation capacity was measured after IRI.

RESULTS: Mice with kidney specific Hmgcs2 deletion had significantly more kidney injury after IRI compared to wild-type controls. Kidneys lacking HMGCS2 exhibited a decrease in ketone content and an increase in lipid droplet accumulation after IRI. Proximal tubular-specific mitochondria lacking HMGCS2 had significantly lower fatty acid oxidation capacity both at baseline and after ischemic injury. Administration of a ketogenic diet for four days prior to IRI was sufficient to decrease kidney injury and augment mitochondrial fatty acid oxidation in kidney Hmgcs2 knockout mice. Kidney tissue lipidomics revealed that the loss of kidney HMGCS2 was associated with a decrease in both arachidonic acid containing phospholipids and prostaglandin levels.

CONCLUSIONS: Loss of renal HMGCS2 and resultant ketogenesis increased ischemia-induced injury and decreased mitochondrial fatty acid oxidation capacity, suggesting a role in renal ketogenesis in limiting acute kidney injury.

PMID:41568909 | DOI:10.1681/ASN.0000001014

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