Id2 haploinsufficiency in mice leads to congenital hydronephrosis resembling that in humans

Congenital hydronephrosis is one of the most common anomalies found in humans and may cause renal failure in childhood. Half of the cases are due to obstruction at the ureteropelvic junction (UPJ). Here we report that mice lacking Id2, an inhibitor of basic helix-loop-helix (bHLH) transcription factors, exhibit hydronephrosis mimicking the characteristics of human cases such as unilaterality and male preponderance. Hydronephrosis was found even in Id2+/- mice. The penetrance was 67.2% in Id2-/- males, 48.8% in Id2+/- males, 28.0% in Id2-/- females and 20.0% in Id2+/- females. Distortion or high insertion of the ureter at the UPJ was frequently observed and these morphological changes were evident in late embryogenesis. Histologically, the muscle layer, where Id2 is normally expressed, was hypertrophic and/or irregular at the UPJ. Furthermore, gene expression analysis suggested that BMP4 (bone morphogenetic protein 4), which is known to be involved in the development of hydronephrosis, appears to function as an upstream factor of Id2. Our results thus raise the possibility that Id2 is a gene responsible for the pathogenesis of hydronephrosis in man.