The ontogeny of the renal calyx and ureter involves the resorption of septa between the ureteric buds, and recanalization of the ureter. Both these phenomena take place in concert with the disappearance of undifferentiated mesenchymal cells which densely surround the ureter and ureteric buds. Our recent studies have revealed that upregulation of AT2 transcriptional activity is temporally and spatially associated with the disappearance of these mesenchymal cells. In vitro studies with mouse embryonic fibroblasts also demonstrated a significant role of AT2 in promoting cell apoptosis. We now report that male mice (129 × C57BL/6) carrying a targeted null mutation of the AT2 gene (on the X chromosome) display congenital urinary tract anomalies (CUTA) with a penetrance of 23%. CUTA is predominantly unilateral, and includes hypoplastic kidney, multicystic dysplastic kidney, ureteropelvic junction obstruction, megaureter, vesicoureteral reflux and some combination thereof. This diversity of phenotypes and male preponderance closely mimic human CUTA. Evaluation of the inheritance pattern of CUTA in mice indicates that at least two other modifier genes are also involved. Together with our recent preliminary genetic findings in human populations, these results indicate that 1) embryonic activation of AT2 receptor has a significant developmental role to ensure normal growth of the ureter and the kidney; and 2) the diverse anatomical patterns seen in childhood CUTA share a common mechanism of impaired/delayed apoptosis of mesenchymal cells surrounding the developing ureter. With the AT2 null mutant mouse, it is now possible to identify other genes, besides the AT2 gene, that are involved in CUTA, and to study the etiology of CUTA in utero.
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Pediatric Research (1998)