Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare
genetic diseases that result from deficiencies in
glyoxylate metabolism. The increased
oxalate synthesis that occurs can lead to
kidney stone formation, deposition of
calcium oxalate in the kidney and other tissues, and
renal failure.
Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of
glyoxylate and could account for a significant portion of the
oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived
oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of
glycolate and
oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more
oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in
glyoxylate reductase/
hydroxypyruvate reductase (GRHPR KO) developed severe
nephrocalcinosis in contrast to animals deficient in
alanine-glyoxylate aminotransferase (AGXT KO) where
nephrocalcinosis was milder and with a lower frequency. Plasma
cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived
glyoxylate to
oxalate. As Hyp catabolism may make a major contribution to the
oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with
calcium oxalate deposition in the kidney.