Chronic renal failure in a mouse model of human adenine
phosphoribosyltransferase deficiency..
Stockelman, Michael G., John N. Lorenz, Frost N. Smith, Gregory P.
Boivin, Amrik Sahota, Jay A. Tischfield, and Peter J. Stambrook.
Department of Cell Biology, Neurobiology and Anatomy, University of
Cincinnati, College of Medicine, Cincinnati, OH 45267-0521.
Department of Molecular and Cellular Physiology, University of
Cincinnati, College of Medicine, Cincinnati, OH 45267-0567.
Department of Pathology and Laboratory Medicine, University of
Cincinnati, College of Medicine, Cincinnati, OH 45267-0529.
Department of Medical and Molecular Genetics, Indiana University
School of Medicine, Indianapolis, IN 46202-5251
APStracts 5:0059F, 1998.
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 weeks,
APRT-deficient male mice are, on average, mildly anemic and smaller
than normal males. They have extensive renal interstitial damage
(assessed by image analysis), elevated blood urea nitrogen (BUN), and
their creatinine clearance rates, measuring excretion of infused
creatinine as an estimate of 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 lifespan,
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 12 weeks age.
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.
Received 25 August 1997; accepted in final form 27 February 1998.
APS Manuscript Number F275-7.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 9 March 1998