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Kidney Week

Abstract: PO0373

The Role of Renal Hmgcs2 in Fasting and Bacterial Inflammation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Venable, Andrea Henning, 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
  • Lee, Lauren Elizabeth, 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
Background

The purpose of inflammatory anorexia during states of acute illness, such as sepsis, remains incompletely understood. We have found that glucose supplementation during bacterial sepsis suppresses ketogenesis and increases mortality, suggesting a potential protective effect of fasting metabolism. Gene expression analysis of the liver and kidney during fasting and after lipopolysaccharide (LPS) challenge, to model sterile bacterial inflammation, revealed that Hmgcs2, the rate-limiting enzyme of ketogenesis, is suppressed in the liver while upregulated in the kidney during LPS sepsis. This expression pattern differs from fasting, during which Hmgcs2 is induced in both the kidney and liver. The significance of renal Hmgcs2 upregulation during bacterial inflammation is unclear.

Methods

Liver-specific Hmgcs2 knockout mice (Alb-CreERT2; Hmgcs2fl/fl), kidney-specific knockout mice (Six2-Cre; Hmgcs2fl/fl),Ppara-/-, and wild-type C57BL/6J mice were fed ad libitum, fasted or injected i.p. with 10 mg/kg LPS. Plasma was analyzed for lipids and ketones. Livers and kidneys were harvested for RNA and protein analysis.

Results

In wild-type mice, circulating ketones increase during fasting and LPS sepsis. While not expressed in the fed state, HMGCS2 protein is induced in the proximal tubules in a PPARa-dependent manner during both fasting and LPS sepsis. Liver-specific Hmgcs2 deletion results in a significant attenuation of circulating ketones during fasting and LPS sepsis, while kidney-specific Hmgcs2 deletion has no effect. Preliminary data show that the loss of Hmgcs2 in the kidney results in an increase in KIM1 protein, a marker indicative of kidney injury, up to 48 hours after LPS injection.

Conclusion

It is well-established that the liver is the main source of circulating ketones. Our data support this notion and demonstrate that although fasting and LPS sepsis induce an upregulation of renal HMGCS2, the expression of this enzyme in the kidney does not appear to contribute to circulating ketones. Our data suggest that while renal HMGCS2 does not produce systemic ketones, it may be important for mitigating kidney injury during LPS sepsis.

Funding

  • NIDDK Support