Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency.
In humans, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency can manifest as nephrolithiasis, interstitial nephritis, and chronic renal failure. APRT catalyzes synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate. In the absence of APRT, 2,8-dihydroxyadenine (DHA) is produced from adenine by xanthine dehydrogenase (XDH) and can precipitate in the renal interstitium, resulting in kidney disease. Treatment with allopurinol controls formation of DHA stones by inhibiting XDH activity. Kidney disease in APRT-deficient mice resembles that seen in humans. By age 12 wk, APRT-deficient male mice are, on average, mildly anemic and smaller than normal males. They have extensive renal interstitial damage (assessed by image analysis) and elevated blood urea nitrogen (BUN), and their creatinine clearance rates, which measure excretion of infused creatinine as an estimate of glomerular filtration rate (GFR), are about half that of wild-type males. APRT-deficient males treated with allopurinol in the drinking water had normal BUN and less extensive visible renal damage, but creatinine clearance remained low. Throughout their lifespans, homozygous null female mice manifested significantly less renal damage than homozygous null males of the same age. APRT-deficient females showed no significant impairment of GFR at age 12 wk. Consequences of APRT deficiency in male mice are more pronounced than in females, possibly due to differences in rates of adenine or DHA synthesis or to sex-determined responses of the kidneys.
Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA.
M G
MG
Stockelman
J N
JN
Lorenz
F N
FN
Smith
G P
GP
Boivin
A
A
Sahota
J A
JA
Tischfield
P J
PJ
Stambrook
D000228:Adenine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000375:Aging; D000493:Allopurinol / Q000627:therapeutic use; D000818:Animals; D002678:Chimera; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D007669:Kidney Calculi / Q000209:etiology / Q000503:physiopathology; D007672:Kidney Cortex / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012016:Reference Values; D012727:Sex Characteristics
D000493:Allopurinol; D003404:Creatinine; D000228:Adenine Phosphoribosyltransferase