Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice

Abstract

SUMMARYVesicoureteric reflux (VUR) is a common congenital defect of the urinary tract that is usually discovered after a child develops a urinary tract infection. It is associated with reflux nephropathy, a renal lesion characterized by the presence of chronic tubulointersitial inflammation and fibrosis. Most patients are diagnosed with reflux nephropathy after one or more febrile urinary tract infections, suggesting a potential role for infection in its development. We have recently shown that the C3H mouse has a 100% incidence of VUR. Here, we evaluate the roles of VUR and uropathogenic Escherichia coli infection in the development of reflux nephropathy in the C3H mouse. We find that VUR in combination with sustained kidney infection is crucial to the development of reflux nephropathy, whereas sterile reflux alone fails to induce reflux nephropathy. A single bout of kidney infection without reflux fails to induce reflux nephropathy. The host immune response to infection was examined in two refluxing C3H substrains, HeN and HeJ. HeJ mice, which have a defect in innate immunity and bacterial clearance, demonstrate more significant renal inflammation and reflux nephropathy compared with HeN mice. These studies demonstrate the crucial synergy between VUR, sustained kidney infection and the host immune response in the development of reflux nephropathy in a mouse model of VUR.

Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development

“…S2) and no anomalies of the bladder. Although embryonic and early postnatal VUR studies in other backgrounds indicate wild-type incidences ranging from 0 to 59% (21)(22)(23), and embryonic and early postnatal VUR in C57/BL6 occurs at low rates (24,25), this is the largest study to date showing background incidence of VUR in C57/ BL6 adult age-matched males. One of the 52 Crkl+/exon2Δ mutants assayed for VUR exhibited unilateral cystic kidney and apparent ureteropelvic junction (UPJ) obstruction as assessed by micro-CT scanning (Fig.…”

Nephrourologic Models and Imaging Methods Used in Preclinical Studies

“…Üreteropelvik bileşke tıkanıklıklarında özellikle renal tübüler hasar meydana gelmektedir. Obstrüktif üropatinin tanısında ultrasonografi, sintigrafi, intravenöz piyelografi ve manyetik rezonans ürografi gibi değişik inceleme yöntemleri kullanılmaktadır (13,14,15,16,17 (21,22).…”

“…Deney hayvanlarının büyük bir kısmında VUR intravezikal üreteral tünel çatısının insizyonuyla oluşturulur. Ayrıca üretral orifis bir klemple kapatılıp mesaneye basınç yapılarak da VUR oluşturulabilir (21,22,23).…”

Renal development in the fetus and premature infant

“…Chronic pyelonephritis and inflammation likely contributes to scarring of renal parenchyma and loss of kidney function [29]. Some studies using mouse models suggest that infection is a key component of renal damage with high grade VUR [30]. However, it remains a source of controversy as, in some cases, high grade VUR in the absence of infection may also lead to progressive renal damage [31].…”