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Kidney Week

Abstract: SA-PO158

Kidney HMGCS2 Protects Against Ischemic Kidney Injury

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Huen, Sarah C., The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Venable, Andrea Henning, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Feola, Kyle C., The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Lee, Lauren Elizabeth, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
Background

Evidence for abnormal renal fatty acid oxidation (FAO) in kidney disease suggests that dysregulated metabolism is a key component of kidney disease pathogenesis. Ketogenesis is a central metabolic pathway in which ketone bodies are produced from FAO. 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

Six2-Cre;Hmgcs2fl/fl (Six2Hmgcs2KO) mice with kidney-specific Hmgcs2 deletion and Hmgcs2fl/fl littermate controls were subjected to ischemia/reperfusion injury (IRI). An acute kidney injury models with right nephrectomy and left IRI was used. Plasma creatinine and/or kidney mRNA/protein expression were assessed 24 hours after IRI. Using novel mouse models with proximal tubular hemagglutinin (HA)-tagged mitochondria with (Ggt1-Cre;Hmgcs2fl/fl;MITO-Tag, GgtHmgcs2KO-MT) or without (Ggt1-Cre;MITO-Tag, Ggt-MT) Hmgcs2 deletion, proximal tubular-specific mitochondria were isolated using anti-HA magnetic beads after unilateral IRI. Fatty acid oxidation (FAO) capacity was measured using palmitoylcarnitine as a substrate and oxygen consumption rate was determined by Seahorse.

Results

Six2Hmgcs2KO mice had significantly higher plasma creatinine levels and expression of kidney injury markers (Kim1) 24 hours after IRI compared to Hmgcs2fl/fl littermate controls. Kidneys lacking HMGCS2 also had an increase in lipid droplet accumulation accompanied by a decrease in Ppargc1a expression, however there was no significant difference in renal de novo lipogenesis gene expression. Proximal tubular-specific mitochondria isolated 24-hour post IRI from Ggt-MT and GgtHmgcs2KO-MT kidneys demonstrated that mitochondria lacking HMGCS2 had significantly lower basal and ADP-stimulated FAO capacity.

Conclusion

Our data provide evidence that proximal tubular HMGCS2 may play an important role in maintaining mitochondrial function and FAO capacity, resulting in protection against ischemic kidney injury.

Funding

  • Other NIH Support