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Kidney Week

Abstract: FR-PO169

Kidney Metabolomics of NHERF1 Deficiency

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Lederer, Eleanor D., The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
  • Gagnon, Kenneth Bradley, The University of Texas Southwestern Medical Center Department of Internal Medicine, Dallas, Texas, United States
Background

Mice lacking NHERF1 (Na+-hydrogen exchanger regulatory factor isoform 1) show increased susceptibility to toxin-induced acute kidney injury (AKI) associated with increased activity of enzymes of the pentose phosphate pathway. We hypothesize that NHERF1 deficiency results in altered kidney cell metabolism associated with enhanced injury response. To test this hypothesis, we performed targeted metabolomic analysis of kidney cortex of wild type (WT) and NHERF1 knockout littermates (KO) in response to saline (vehicle; V) or cisplatin (C).

Methods

5 WT and 5 KO littermate mice underwent IP injection with either saline or 20 mg/kg body weight of cisplatin (n=20). Kidneys were harvested after 72 h for metabolite extraction with HPLC-grade methanol. Ultrahigh-performance liquid chromatography tandem mass spectrometry performed by the UTSW Metabolomics Core within the Dept of Biochemistry identified over 140 metabolites in the four experimental groups: WTV; WTC; KOV; and KOC.

Results

Principal component analysis demonstrated significant variance between all four experimental groups implicating both NHERF1 absence and cisplatin-induced AKI in metabolic shift. A clear separation was seen between WTV and KOV. Enrichment and Pathway Analysis comparing WTV/KOV demonstrated enrichment of metabolites associated with methylhistidine and glycerophospholipid metabolism, phosphatidylcholine biosynthesis, and the pentose phosphate pathway. After cisplatin, major differences were noted between WTC and KOC in metabolites associated with lipid and phospholipid biosynthesis, nucleotide sugar metabolism, and mitochondrial electron transport chain.

Conclusion

NHERF1 deficiency alters carbohydrate and lipid metabolism similar to what is seen in response to kidney disease such as diabetes and uninephrectomy and alters metabolic response to injury. Whether these metabolic changes are due to deficient nutrient uptake or altered intracellular pathway integrity and how these changes predispose to acute injury are unknown.

Funding

  • Veterans Affairs Support