Background. We have developed a knockout mouse model for adenine phosphorib
osyltransferase (APRT) deficiency, a condition that often leads to 2,8-dihy
droxyadenine (DHA) nephrolithiasis in humans. Aprt knockout male mice devel
op severe renal damage by three months of age, but this is strain specific.
Renal damage in female mice is less pronounced than in males. The gene lev
el changes that promote renal injury in APRT-deficient mice are not known.
Methods. We used mRNA differential display polymerase chain reaction (DD-PC
R) to analyze renal gene expression changes in APRT-deficient male and fema
le mice (strain C3H) compared with age- and sex-matched Aprt heterozygote c
ontrols. The differentially amplified bands were reamplified, cloned, seque
nced, and queried against the National Center for Biotechnology Information
nonredundant databases using the Basic Alignment Search Tool. Relative qua
ntitative reverse transcription-polymerase chain reaction was used to confi
rm the results of DD-PCR for a selected number of genes in one-, three-. an
d six-month-old male and female mice.
Results. Sixty-three differentially amplified bands were identified, includ
ing 21 for known genes, and 8 of these were examined further. In three-mont
h-old APRT-deficient male mice. the expression of C10 was increased tenfold
, and there was a fourfold to sevenfold increase in the expression of a dis
integrin and metalloproteinase with thrombospondin motifs (ADAMTS-1), MGP (
matrix Gla protein), and lysyl oxidase (LOX). The expression of cholecystok
inin-A receptor (CCKAR), imprinted multimembrane-spanning polyspecific tran
sporter-like gene 1 (IMPT-1), and kidney androgen-regulated protein (I(AP)
was diminished twofold to fourfold. but there was little or no change in th
e expression of organic anion transporter (OATP). Except for a more than te
nfold increase in C10 expression and up to tenfold decrease in KAP expressi
on, APRT-deficient female mice did not show significant changes in gene exp
ression compared with controls.
Conclusions. These findings suggest that (1) there are sex-related differen
ces in gene expression in DMA lithiasis, possibly caused by increased depos
ition of DHA crystals in male compared with female kidneys; and (2) the exp
ression of certain genes (for example, C10) may simply be an indication of
nonspecific cellular stimulation and may not be related to renal injury.