Hydroxyproline metabolism in mouse models of primary hyperoxaluria.

[primary hyperoxaluria type 1]

Primary hyperoxaluria type 1 (PH 1 ) and type 2 (PH 2 ) 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 PH 1 and PH 2 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 .

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Diseases presenting "agxt ko animals" symptom

primary hyperoxaluria type 1

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