Overexpression of RET leads to vesicoureteric reflux in mice

Abstract

, a tyrosine kinase receptor essential for kidney development, has recently been shown to be important for the formation of the urinary tract. When RET is overexpressed in the HoxB7/Ret transgenic mouse, kidneys are small and cystic, and in some of the mice, the ureters are grossly dilated. Here, we report that the observed ureteral dilatation is associated with the urinary tract abnormality vesicoureteric reflux (VUR), in which urine flows retrogradely from the bladder to the ureter. Reflux was determined in vitro by injecting methylene blue into the bladders of HoxB7/Ret and wild-type mice. At postnatal day 1, 30% of HoxB7/Ret mice had VUR compared with 4% of wild-type mice (P Ͻ 0.05). The length of the intravesical ureteral tunnel was shorter in HoxB7/Ret mice compared with wild-type mice, on both the right and the left sides (P Ͻ 0.05), suggesting a basis for the higher incidence of VUR in these mutants. At embryonic day 11, the ureteric bud was found to exit more caudally from the mesonephric duct in HoxB7/Ret mice, and this may predispose them to VUR (P Ͻ 0.05). Wild-type and HoxB7/Ret mice were tested for reflux at embryonic day 17, and both showed a high frequency of VUR (59 and 75%, respectively). These results suggest that VUR may occur transiently during normal urinary tract development before the ureter has completed its insertion into the bladder. In the HoxB7/Ret mouse, overexpression of RET appears to delay the maturation of the distal ureter, resulting in postnatal VUR. The HoxB7/Ret mouse is thus an important model in which to examine how vesicoureteric reflux arises during urinary tract development. kidney defect; urinary tract defect; ureteric bud PRIMARY VESICOURETERIC REFLUX (VUR) is a urinary tract abnormality in which urine flows retrogradely from the bladder to the ureters because of an anatomic defect at the junction of the ureter and the bladder. It affects 1-2% of children and predisposes them to recurrent urinary tract infections and in some cases, end-stage renal disease (7, 33). The condition is hereditary: it frequently affects multiple family members, and several genetic loci have been identified from linkage studies of affected families (5, 6).VUR is normally prevented by a functional valve, the flap-valve mechanism, that forms at the site of the ureteral insertion into the bladder. The flap-valve is dependent on 1) the tunnel in which the ureter enters into the bladder, 2) the presence of a muscular layer within the bladder and the ureter, and 3) the position of the ureteral orifice in the muscular layer within the bladder (the trigone). When the bladder is distended with urine, the tunnel is compressed, and this prevents the retrograde passage of urine from the bladder to the kidneys.The length of the intravesical ureteral tunnel is critical for the flap-valve mechanism: shorter tunnels have been identified in patients with VUR (17, 32). Other anatomic findings that have been associated with VUR include a lack of musculature within the ureter and its tunnel (30) and a ureteral ...

The development of the bladder trigone, the center of the anti-reflux mechanism

“…A shortening of the intramural segment, or ureter orifices joining the trigone abnormally, can be caused by sprouting of the ureteric bud from the Wolffian duct from a location more cranial or caudal than normal (Mackie and Stephens, 1975;Pope et al, 1999;Stephens, 1983) as seen in several mouse models (Basson et al, 2005;Batourina et al, 2005;Grieshammer et al, 2004;Kume et al, 2000;Lu et al, 2007;Miyazaki et al, 2000;Yu et al, 2004), or by abnormalities in ureter transposition, at the time when the ureter normally separates from the Wolffian duct (Batourina et al, 2005). Intrinsic ureteral abnormalities, such as a failure in muscle differentiation, can also result in reflux owing to faulty urine transport or peristalsis (Airik et al, 2006;Chang et al, 2004;Yu et al, 2002).…”

Genetics of vesicoureteral reflux

“…the phenotype of this model is thought to corroborate the hypothesis that abnormal ureteric bud position disrupts ureterovesical junction formation. 66 similarly, reduced PaX2 signaling caused by a heterozygous Pax2 mutation has been shown to result in shortened intravesical ureters, caudally shifted ureteric buds, reduced bud branching, small hypoplastic kidneys with reduced nephron number and particularly vur. 51,67 the transcription factor Lim1 (also known as homeobox protein Lhx1) is a homeobox gene expressed in the organizer region of mouse embryos.…”

RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

“…Although there is only limited evidence that links mutations in Ret to kidney and urinary tract malformations in humans [Loré et al, 2000[Loré et al, , 2001 and Ret mutations have not been identified in the only VUR family studied [Shefelbine et al, 1998], several investigations with animal models suggested that Ret dysfunction may be responsible for UB branching, distal ureter abnormalities, and VUR [Shakya et al, 2005;Yu et al, 2004, Batourina et al, 2002Schuchardt et al, 1996]. UB outgrowth is inhibited in ret-null mice; however, their metanephric mesenchyme is still responsive to inductive signals [Murawski and Gupta, 2006;Costantini and Shakya, 2006;Pachnis et al, 1993].…”