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

Abstract

Kota L, Schulz H, Falak S, Hübner N, Osborne-Pellegrin M. Localization of genetic loci controlling hydronephrosis in the Brown Norway rat and its association with hematuria. Physiol Genomics 34: 215-224, 2008. First published June 3, 2008 doi:10.1152/physiolgenomics.00221.2007.-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 ϫ (BN ϫ 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.

Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits

“…The results are consistent with the hypotheses that HN is correlated with body weight and is not the primary cause of renal disease in this model. Our results are also consistent with the study of Kota et al (15), who observed a correlation of HN with body weight in male BN rats.…”

“…QTL mapping of the BN HN phenotype in a cross with the LOU rat strain revealed a QTL on chromosome 6 without any suggestive effects on chromosome 1 (15). We quantitated HN in our F2 intercross animals.…”

“…Using the scale and scoring method of Kota et al (15), we estimated the percent of dilation of the renal pelvis and assigned an HN score between 0 and 10. We assigned 0 to kidneys that appeared to be without HN, 0.5 or 1 to kidneys that were suspicious of having mild pelvic dilation, and 8 -10 to kidneys with severe HN and were essentially hollow.…”

“…Congenic strains can be selected to contain previously identified QTLs and have been used as tools for additional studies leading to identification of the underlying gene. Many studies have reported isolation of congenic mouse and rat strains exhibiting renal disease associated with hypertension, autoimmunity, and even diabetes (14,15). However, few congenic studies have examined the relationship of obesity with renal disease.…”

Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains

“…C: kidney section images (ϫ20) taken under polarized light to distinguish the birefringent crystal deposits from background. does exhibit mild hydronephrosis and some abnormal arterial phenotypes (e.g., IEL rupture, PDA, aortic elastin deficit) (18,19). Due to the genetic predisposition of the SS rat to develop hypertension and renal injury, it might be expected that the SS rat would be more susceptible to develop kidney stones.…”