Pathogenesis of Renal Injury in the Megabladder Mouse: A Genetic Model of Congenital Obstructive Nephropathy

Abstract

Congenital obstructive nephropathy (CON) is the most common cause of chronic renal failure in children, often leading to end stage renal disease. The megabladder (mgb) mouse exhibits signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure following birth. This study examined the development of progressive renal injury in homozygous mgb mice (mgb−/−). Renal ultrasound was utilized to stratify the disease state of mgb−/− mice, while surgical rescue was performed using vesicostomy. The progression of renal injury was characterized using a series of pathogenic markers including α-smooth muscle isoactin (α-SMA), TGF-β1, connective tissue growth factor (CTGF), E-cadherin, F4/80, Wilm’s Tumor 1 (WT-1), and paired box gene 2 (Pax2). This analysis indicated that mgb−/− mice are born with pathologic changes in kidney development that progressively worsen in direct correlation with the severity of hydronephrosis. The initiation and pattern of fibrotic development observed in mgb−/− kidneys appeared distinctive from prior animal models of obstruction. These observations suggest that the mgb mouse represents a unique small animal model for the study of CON.

Congenital Obstructive Nephropathy: Clinical Perspectives and Animal Models

“…Megabladder mice closely mirror the pathophysiology associated with a lower urinary tract obstruction in several key respects (Ingraham, et al, 2010;Singh, et al, 2007). Mgb-/-mice develop a functional obstruction of the lower urinary tract that leads to hydroureteronephrosis during embryogenesis.…”

“…In severe cases, fibrosis ultimately extends throughout the renal parenchyma. Altered patterns of -smooth muscle isoactin (-SMA), E-cadherin, TGF-1 and connective tissue growth factor expression are also observed in mgb-/-kidneys, supporting a role for these pathways in the development of fibrosis associated with congenital obstructive nephropathy (Ingraham, et al, 2010). Severely affected mgb-/-kidneys also display several dysplastic features including alteration in the developmental distribution of WT1 and PAX2.…”

“…Our laboratory has identified a unique transgenic mouse model of congenital obstructive nephropathy designated the megabladder (mgb) mouse (Ingraham et al, 2010;Singh et al, 2007). As shown in Figure 7, these mice develop a nonfunctional, over-distended bladder due to a bladder-specific defect in smooth muscle differentiation.…”

Current perspectives on congenital obstructive nephropathy

“…Although mgb-/-mice do not possess PUV, the most common cause of bilateral CON in humans, the mice closely mirror the pathophysiology associated with a lower urinary tract obstruction [92,93]. First, mgb-/-mice develop a nonanatomic functional obstruction of the lower urinary tract in utero, resulting in the development of hydroureteronephrosis during late embryogenesis.…”

Avaliação dos valores séricos e urinários de CA 19-9 e TGFbeta1 na obstrução parcial e completa de ureteres em ratos

“…Muitas espécies animais foram utilizadas em modelos de obstrução ureteral completa e parcial incluindo o rato (Chevalier et al, 1998;Yeh et al, 2011;Morsing et al, 1987;Guerin et al, 2008), coelho (Cheng et al, 1993), porco (Dissing et al, 2001;Eskild-Jensen., 2002), cão (Shokeir et al, 1995;Matsui et al, 1986;Harada et al, 1992;Ryan et al, 1987), ovelha e macaco (Wen et al, 2002), entre outros. A maioria desses modelos foi induzida após o nascimento, porém alguns modelos com uropatias obstrutivas congênitas foram utilizados (Miller et al, 2004;Ingraham et al, 2010). Modelos antenatais também foram criados para simular uropatias obstrutivas que se iniciam durante a nefrogênese ou em animais que apresentam nefrogênese incompleta após o nascimento .…”