Localization of genetic loci controlling hydronephrosis in the Brown Norway rat and its association with hematuria

The aim of this study was to investigate the genetic basis of congenital hydronephrosis (HN), a poorly defined pathological entity, with a rat model. The Brown Norway (BN) strain spontaneously presents a high incidence of apparently asymptomatic HN, whereas the LOU strain does not. A backcross was established between these two strains [BN x (BN x LOU)] and a genomewide scan was performed with 193 microsatellite markers on 121 males and 118 females of this population, which had been phenotyped and scored for HN severity (defined as degree of renal pelvic dilation), followed by linkage analysis with Mapmaker/QTL software. Bilateral HN score was significantly linked to a locus on chromosome 6 (Z scores 4.4 and 4.8 for all rats and for females, respectively). Suggestive loci were identified on chromosomes 2 (for only right-sided HN) and 4. This is the first study in rats to identify genetic loci for HN. Three candidate genes present in these loci were sequenced and insertions detected in Id2 and Agtr1b genes in BN, which did not, however, lead to modified expression as measured by quantitative PCR. Production of a congenic line for part of the chromosome 6 locus confirmed its involvement in HN, but the phenotype was mild. Evidence of hematuria was observed in 9.6% of the backcross rats, mostly males and only in kidneys with HN, but not necessarily in the most severely affected. Hematuria also occurs in the BN colony used here, where it is due to papilloma-like lesions involving pelvic epithelial proliferation, but not in the LOU rat.