Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 1 in 500 births and are a major cause of morbidity in children. Notably, CAKUT account for the most cases of pediatric end-stage renal disease and predispose the individual to hypertension and cardiovascular disease throughout life. Although some forms of CAKUT are a part of a syndrome or are associated with a positive family history, most cases of renal system anomalies are sporadic and isolated to the urinary tract. Broad phenotypic spectrum of CAKUT and variability in genotype-phenotype correlation indicate that pathogenesis of CAKUT is a complex process that depends on interplay of many factors. This review focuses on the genetic mechanisms (single-gene mutations, modifier genes) leading to renal system anomalies in humans and discusses emerging insights into the role of epigenetics, in utero environmental factors, and micro-RNAs (miRNAs) in the pathogenesis of CAKUT. Common gene networks that function in defined temporospatial fashion to orchestrate renal system morphogenesis are highlighted. Derangements in cellular, molecular, and morphogenetic mechanisms that direct normal renal system development are emphasized as a major cause of CAKUT. Integrated understanding of how morphogenetic process disruptions are linked to CAKUT will enable improved diagnosis, treatment, and prevention of congenital renal system anomalies and their consequences.

Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3–6 per 1000 live births, account for the most cases of pediatric end-stage kidney disease (ESKD), and predispose an individual to hypertension and cardiovascular disease throughout life. Although CAKUTs are a part of many known syndromes, only few single-candidate causative genes have been implicated so far in nonsyndromic cases of human CAKUT. Evidence from mouse models supports the hypothesis that non-syndromic human CAKUT may be caused by single-gene defects. Because increasing numbers of children with CAKUT are surviving to adulthood, better understanding of the molecular pathogenesis of CAKUT, development of new strategies aiming at prevention of CAKUT, preservation of renal function, and avoidance of associated cardiovascular morbidity are needed. In this paper, we will focus on the knowledge derived from the study of syndromic and non-syndromic forms of CAKUT in humans and mouse mutants to discuss the role of genetic, epigenetic, and in utero environmental factors in the pathogenesis of non-syndromic forms of CAKUT in children with particular emphasis on the genetic contributions to CAKUT.

A growing body of evidence supports the concept that changes in the intrauterine milieu during “sensitive” periods of embryonic development or in infant diet after birth affect the developing individual, resulting in general health alterations later in life. This phenomenon is referred to as “developmental programming” or “developmental origins of health and disease.” The risk of developing late-onset diseases such as hypertension, chronic kidney disease (CKD), obesity or type 2 diabetes is increased in infants born prematurely at <37 weeks of gestation or in low birth weight (LBW) infants weighing <2,500 g at birth. Both genetic and environmental events contribute to the programming of subsequent risks of CKD and hypertension in premature or LBW individuals. A number of observations suggest that susceptibility to subsequent CKD and hypertension in premature or LBW infants is mediated, at least in part, by reduced nephron endowment. The major factors influencing in utero environment that are associated with a low final nephron number include uteroplacental insufficiency, maternal low-protein diet, hyperglycemia, vitamin A deficiency, exposure to or interruption of endogenous glucocorticoids, and ethanol exposure. This paper discusses the effect of premature birth, LBW, intrauterine milieu, and infant feeding on the development of hypertension and renal disease in later life as well as examines the role of the kidney in developmental programming of hypertension and CKD.

Angiotensinogen-, angiotensin-converting enzyme-, and angiotensin II (Ang II) type 1 receptor (AT 1 R)-deficient mice exhibit a dilated renal pelvis (hydronephrosis) and a small papilla. These abnormalities have been attributed to impaired development of the ureteral and pelvic smooth muscle. Defects in the growth and branching of the ureteric bud (UB), which gives rise to the collecting system, have not been examined carefully. This study tested the hypothesis that Ang II stimulates UB growth and branching in the intact metanephros. Immunohistochemistry demonstrated that embryonic mouse kidneys express AT 1 R in the UB and its branches. Embryonic day 11.5 metanephroi were microdissected from Hoxb7-green fluorescence protein mice and grown for 48 h in serum T he metanephros develops via reciprocal inductive interactions between the ureteric bud (UB) and the metanephrogenic mesenchyme (MM) (1,2). Signals from the MM induce UB outgrowth from the nephric duct and its elongation and entrance into the mesenchyme followed by repetitive branching to form the renal collecting system (ureter, pelvis, calyces, and collecting ducts). In turn, emerging UB tips induce surrounding mesenchymal cells to condense, aggregate, undergo mesenchymal-to-epithelial transition, and form nephrons (from the glomerulus to the distal tubule). Therefore, UB branching morphogenesis is critical in determining nephron number, and subtle defects in the efficiency and/or accuracy of this process potentially can have profound effects on the proper development of the metanephric kidney. Decreased nephron endowment is linked to hypertension and eventual progression to chronic renal failure (3,4). In addition, aberrant UB branching morphogenesis causes renal dysplasia, the leading cause of chronic renal failure in human infants.Genetic inactivation of the renin-angiotensin system (RAS) genes in mice causes abnormalities in the development of the ureter, renal pelvis, and papilla (5-9). Angiotensinogen-, angiotensin-converting enzyme (ACE)-, or angiotensin II (Ang II) type 1 receptor (AT 1 R)-deficient mice exhibit pelvic dilation (hydronephrosis) and a small papilla mimicking urinary tract obstruction. Elegant studies from Ichikawa's laboratory have suggested that absence of AT 1 R signaling in ureteral smooth muscle cells impairs pelvic-ureteral smooth muscle development and peristalsis (9). Mutations in the AT 2 R gene in mice and humans are associated with increased incidence of lower urinary tract anomalies, including double ureters and vesicoureteral reflux (10). These findings indicate that UB growth and development are a target for Ang II actions. Work that has performed by several laboratories, including ours, has revealed that the fetal kidney expresses a local RAS. Quantitative analysis of murine Ang II receptors AT 1 R and AT 2 R gene expression indicate that AT 1 R undergo a progressive increase during fetal and neonatal life, whereas AT 2 R are high in the fetus and decline significantly with maturation (11). Immunolocalization studies d...

Mutations of the renin-angiotensin system (RAS) genes are associated with congenital abnormalities of the kidney and urinary tract. We have shown that angiotensin (Ang) II stimulates ureteric bud (UB) branching in vitro. The present study tested the hypothesis that Ang II stimulates the GDNF/c-Ret/Wnt11 pathway. E12.5 mice metanephroi were grown for 24 hours in the presence or absence of Ang II or AT1R receptor antagonist candesartan and subjected to whole-mount ISH. c-Ret, a receptor tyrosine kinase for GDNF, and its downstream target Wnt11 were induced by Ang II in the UB tip cells. GDNF, a Wnt11-regulated gene expressed in the mesenchyme, was also upregulated by Ang II. In contrast, Ang II treatment downregulated Spry1, an endogenous inhibitor of Ret tyrosine kinase activity, in an AT1R-dependent manner. Quantitative RT-PCR analysis confirmed that Ang II decreases Spry1 mRNA levels in cultured UB cells. In vivo BrdU incorporation indicated that exogenous Ang II preferentially stimulates UB tip cell proliferation, while AT1R blockade increases TUNEL-positive apoptotic cells. These findings suggest a model in which AT1R-mediated inhibition of Spry1 gene expression releases c-Ret tyrosine kinase activity leading to upregulation of c-Ret and its downstream target gene, Wnt11. Enhanced Wnt11 expression induces GDNF in the adjacent mesenchyme. This causes focal bursts of UB tip cell proliferation, a decrease in UB tip cell apoptosis and branching.