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Abstract: SA-PO106

Kidney HMGCS2 Protects Against Ischemic Kidney Injury

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


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

Chronic kidney disease (CKD) is a growing global health problem. 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.


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 and mitochondrial respiration was determined by Seahorse. 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 (AKI) model with right nephrectomy and left IRI and a chronic kidney disease (CKD) model with unilateral IRI were used. Plasma creatinine and/or kidney mRNA expression was assessed 24 hours (AKI) and 14 days (CKD) after IRI.


Proximal tubular-specific mitochondria isolated from 24-hour fasted Ggt-MT and GgtHmgcs2KO-MT mice demonstrated that mitochondria lacking HMGCS2 had significantly lower basal and ADP-stimulated Complex I and II activity as measured by mitochondrial oxygen consumption rate. Compared to littermate controls, Six2Hmgcs2KO mice had significantly higher plasma creatinine levels and expression of the kidney injury marker Kim1 after AKI. In the CKD model, inflammation (Tnfa) was significantly elevated and markers of fibrosis (Col1a1, Col4a1, Tgfb1) trended higher in Six2Hmgcs2KO injured kidneys.


Our data provide evidence that proximal tubular HMGCS2 may play an important role in maintaining mitochondrial function and protecting against ischemic kidney injury.


  • NIDDK Support