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Abstract: FR-PO313

Gender Difference in Plasma and Urinary Oxalate Levels in a Mouse Model for Primary Hyperoxaluria Type 1

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Hassan, Hatim A., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Baranwal, Gaurav, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Subramaniam, Marina, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Arukha, Ananta Prasad, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Shaikh, Soorih, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Subahi, Mohamed, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • El Nayir, Mohammed H., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Regalia, Destiny, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Al Dawood, Dawood, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Dumenya, Mmanuel Afi, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Roy-Chowdhury, Jayanta, Albert Einstein College of Medicine, Bronx, New York, United States
Background

Mutations in the alanine–glyoxylate amino transferase gene (Agxt) cause primary hyperoxaluria type I (PH1). A mouse model for PH1 was previously reported, with males having ~17.6% higher urine oxalate compared to females.

Methods

mRNA and protein expression levels were assessed by qPCR and immunoblotting.

Results

We now observed that males have significantly higher (~1.7-fold) urine oxalate compared to females (24-h urine oxalate in µg/g body weight: wild-type = 1.60±0.18; males = 6.69±0.32; females = 3.89±0.14). Males also have significantly higher (2.1-fold) plasma oxalate (µM: males = 4.86±0.86; females = 2.35±0.39). We first confirmed that the observed gender difference in oxalate levels is not due to differences in genotyping by showing that both males and females are homozygous for Agxt-/-. Anion transporters SLC26A1 (A1) and SLC26A6 (A6) play important roles in oxalate homeostasis. Proximal tubular oxalate secretion involves oxalate entry into the cell from blood via A1, and then its secretion into the urine via A6. A gender difference in liver and kidney A1 protein expression exists (with no change in mRNA), where higher A1 expression is observed in male compared to female rats and is associated with significantly higher plasma (~1.8-fold) and urine (~2-fold) oxalate levels in males (including high renal oxalate secretion). Male rats also have higher liver sulfate-oxalate exchange, which could lead to elevated plasma oxalate. We therefore examined whether gender differences in A1 and/or A6 expression contribute to the observed differences in urine and plasma oxalate levels in PH1 mice. Compared to males, females have significantly reduced kidney A6 mRNA (44.6%, using qPCR) and total glycosylated A6 protein (>40%) expression. There were no significant differences in liver and kidney (~19% reduction) A1 mRNA expression levels. We could not assess A1 protein expression due to lack of working antibodies, with reduced expression expected based on data from rats.

Conclusion

We conclude that male PH1 mice have significantly higher urine and plasma oxalate levels compared to females, and that differences in kidney A6 and/or A1 (liver and/or kidney) expression potentially contribute to the observed gender difference.