Altered gene expression in kidneys of mice with 2,8-dihydroxyadenine nephrolithiasis

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.