Augmented and accelerated nephrogenesis in TGF-beta 2 heterozygous mutant mice

Several members of the transforming growth factor-P (TGF-beta) superfamily play key roles in kidney development, either directly or indirectly regulating nephron number. Although low nephron number is a risk factor for cardiovascular and renal disease, the implications of increased nephron number has not been examined due to the absence of appropriate animal models. Here, using unbiased stereology we demonstrated that kidneys from TGF-beta 2 heterozygous (TGF-beta 2(+/-)) mice have approximately 60% more nephrons than wild-type mice at postnatal day 30. To determine whether augmented nephron number involved accelerated ureteric branching morphogenesis, embryonic day 11.5 metanephroi were analyzed via confocal microscopy. A 40% increase in total ureteric branch length was observed in TGF-beta 2(+/-) kidneys, together with an extra generation of branching. In embryonic day 12.5 metanephroi cultured for 48 h the numbers of both ureteric tree tips and glomeruli were significantly greater in TGF-beta 2(+/-) kidneys. These findings suggest that augmented nephron number in TGF-beta 2(+/-) kidneys results from accelerated ureteric branching morphogenesis and nephron formation. Manipulation of TGF-beta 2 signaling in vivo may provide avenues for protection or rescue of nephron endowment in fetuses at risk.