The C3H/HeJ inbred mouse is a model of vesico-ureteric reflux with a susceptibility locus on chromosome 12

Abstract

Vesico-ureteric reflux is the most common congenital anomaly of the urinary tract, characterized by a defective uretero-vesical junction with retrograde urine flow from the bladder toward the kidneys. Because there is strong evidence for a genetic basis for some cases of vesico-ureteric reflux, we screened 11 inbred mouse strains for reflux and kidney size and identified one strain, C3H/HeJ, that has a 100 percent incidence of vesico-ureteric reflux with otherwise normal kidneys at birth. These mice are predisposed to reflux as a result of a defective uretero-vesical junction characterized by a short intravesical ureter. This defect results from a delay in urinary tract development initially manifested by a ureteric bud arising from a more caudal location along the mesonephric duct. In contrast, C57BL/6J mice (resistant to reflux at birth) have long intravesical ureters, normally positioned ureteric buds, and no delay in urinary tract development. Genome-wide and additional fine mapping of backcross mice, derived from C3H/HeJ and C57BL/6J crosses, identified a significant reflux susceptibility locus, Vurm1, on chromosome 12 (peak logarithm of the odds=7.39). The C3H/HeJ mouse is a model of vesico-ureteric reflux without renal malformation, and further characterization of this model will allow for the identification of a pathway important for urinary tract development, a finding that will serve as a model for the human disorder.

α–Intercalated cells defend the urinary system from bacterial infection

“…Since there was little evidence of colonization of the C57BL/6 kidney with UPECs in our model of UTI, we turned to another model of urinary infection: pyelonephritis in the C3H/HeN mouse. These mice are susceptible to UPEC-mediated pyelonephritis because they are naturally prone to vesiculoureteral reflux due to the Vurm1 locus (83,84). We confirmed the reflux using bioluminescent CFT073 UPEC-lux, which rapidly ascended to the kidney ( Figure 4, E and F).…”

Vesico-ureteric reflux: using mouse models to understand a common congenital urinary tract defect

“…Similar to Hoxb7/Ret +/− and Pax2 1Neu+/− mice, C3H/HeJ mice have significantly shorter intravesical ureters and caudally positioned ureteric buds compared with inbred mouse strains that do not have VUR (i.e., C57BL/6J mice) [84]. The caudally positioned ureteric bud has been linked to a delay in urinary tract development in two mouse models of VUR, the Pax2 1Neu+/− and the C3H/ HeJ mouse.…”

“…The VUR phenotype in the C3H/HeJ mouse has been mapped to a locus, Vurm1, on the proximal end of mouse chromosome 12 [84]. Interestingly, this locus appears to work in conjunction with other modifier loci elsewhere in the genome, further emphasizing the genetic complexity of VUR [84]. The Vurm1 locus is syntenic to human chromosome 2p24, which was recently identified in a whole genome linkage and association study of families with VUR from the UK and Slovenia [39].…”

“…To date, six mouse models of VUR have been identified with renal normoplasia: DDD, C3H/HeN, C3H/HeJ, DBA/2J, CBA/J, and AKR/J (Fig. 3, Table 1) [83,84]. The DDD mouse was the first inbred mouse model of VUR described [83].…”

“…To date, only the C3H/HeJ mouse with a 100% incidence of VUR at birth has been genetically characterized. The VUR phenotype in the C3H/HeJ mouse has been mapped to a locus, Vurm1, on the proximal end of mouse chromosome 12 [84]. Interestingly, this locus appears to work in conjunction with other modifier loci elsewhere in the genome, further emphasizing the genetic complexity of VUR [84].…”