Kidney Week

Abstract: FR-PO552

Gout Risk Variant ABCG2 Q141K Alters Renal Amino Acid Metabolism and Alpha-Ketoglutarate

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Woodward, Owen M., University of Maryland School of Medicine, Baltimore, Maryland, United States

Owen M. Woodward, PhD

• Li, Yong, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany

Yong Li, PhD

• Halperin Kuhns, Victoria L., University of Maryland School of Medicine, Baltimore, Maryland, United States

Victoria L. Halperin Kuhns, PhD

• Zapf, Ava M., University of Maryland School of Medicine, Baltimore, Maryland, United States

Ava M. Zapf, PhD

• Kottgen, Anna, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany

Anna Kottgen, MD, MPH

Background

ABCG2 is an epithelial and proximal tubule efflux transporter. A common missense variant, Q141K, increases hyperuricemia and gout risk. GWAS studies identified associations of ABCG2 SNPs and HbA1c levels, BMI, LDL, creatinine, and C-reactive protein, suggesting a metabolic role for ABCG2. The relationship between ABCG2, renal function, urate and metabolic disease remains unclear.

Methods

We conducted a metabolomic study on paired plasma and urine samples of 1033 carriers and 3879 non-carriers of Q141K ABCG2 participating in the GCKD study. To dissect causal mechanisms for observed differences, i.e. ABCG2 dysfunction versus hyperuricemia, similar paired metabolomics as well as whole-kidney RNA-seq data were generated from two hyperuricemia mouse models: the orthologous Q140K Abcg2, and an inducible uricase knockout, Uox-iKO.

Results

Enriched pathways based on altered metabolites identified in both human and mouse ABCG2 variants were highly correlated (plasma r=0.83; p=2.4x10^-54, urine r=0.7; p=8.47x10^-32), supporting the use of the Q140K Abcg2 model to study mechanisms in humans. In urine, the strongest enrichment of metabolites comparing Q141K carriers and non-carriers was observed for urate and related pathways, including organic nitrogen compounds. The most significant non-urate containing pathways were carboxylic acids (FDR-p=3.02x10^-9) and organic acid derivates (FDR-p=2.87x10^-6). To discern a role for ABCG2 in renal function, we focused on metabolites in these pathways that were only altered in urine of human Q141K ABCG2 carriers, and found lower polyamine, urea cycle metabolites and alpha-ketoglutarate (AKG; all p<0.05). The Q140K Abcg2 mice also displayed lower urinary polyamine metabolites and AKG. Kidney RNA-seq found significantly altered key genes of the polyamine and urea cycle in Q140K Abcg2 mice: Agr2 and Cpt1 and AKG transporter SLC13A3. In contrast, Uox iKO mice showed higher urinary polyamide, urea cycle metabolites and AKG along with altered expression of the AKG receptor Oxgr1 and the HCO3-/Cl- exchanger Slc26a4 (pendrin). Physiological data suggested increased urinary AKG altered plasma HCO3- in the Uox iKO mice, consistent with OXGR1 activation of pendrin.

Conclusion

Combination of orthologous human and mouse metabolomic data suggests a role for ABCG2 in regulating proximal tubule amino acid metabolism and AKG.

Funding

• NIDDK Support