Hydroxyproline metabolism in mouse models of primary hyperoxaluria

Area of Science:

• Biochemistry
• Genetics
• Nephrology

Background:

• Primary hyperoxaluria types 1 and 2 (PH1, PH2) are rare genetic disorders impacting glyoxylate metabolism.
• Elevated oxalate synthesis in PH leads to kidney stones, calcium oxalate deposition, and renal failure.
• Hydroxyproline (Hyp) catabolism is a significant source of glyoxylate, potentially contributing to oxalate production in PH.

Purpose of the Study:

• To investigate the sensitivity of PH1 and PH2 mouse models to oxalate derived from Hyp catabolism.
• To assess the role of specific enzyme deficiencies in Hyp-induced nephrocalcinosis and renal dysfunction.

Main Methods:

• Mice models of PH1 (AGXT KO) and PH2 (GRHPR KO) were fed a diet containing 1% Hydroxyproline (Hyp).
• Urinary glycolate and oxalate excretion were monitored to track Hyp catabolism.
• Kidney pathology and plasma cystatin C levels were assessed to evaluate nephrocalcinosis and renal function.

Main Results:

• Both AGXT KO and GRHPR KO mice exhibited increased oxalate excretion compared to wild-type (WT) mice when fed Hyp.
• GRHPR KO mice developed severe nephrocalcinosis and significant renal function loss after Hyp feeding.
• AGXT KO mice showed milder nephrocalcinosis and no significant renal function loss, similar to WT mice.

Conclusions:

• Kidney GRHPR activity is crucial for limiting the conversion of Hyp-derived glyoxylate to oxalate.
• GRHPR deficiency exacerbates kidney damage from Hyp-induced oxalate production in PH.
• These mouse models are valuable for studying calcium oxalate deposition mechanisms in PH.