Renal abnormalities and their developmental origin

The kidney is a central organ of the mammalian organism that, apart from blood filtration, is essential for the control of blood pressure and pH.Congenital abnormalities of the kidneys and the urinary tract (CAKUT) are among the most frequent abnormalities in the newborn child, and often lead to renal failure in adult life.Understanding kidney development is crucial to comprehending the molecular basis of CAKUT syndrome in humans, and to developing future therapeutic interventions, such as cell-replacement therapies and the growth of renal organs in vitro.Central to the induction of the metanephros (permanent kidney) is the glial-derived neurotrophic factor (GDNF)–RET signalling pathway. Complex molecular networks tightly control GDNF expression, and restrict it to the presumptive metanephric mesenchyme to ensure outgrowth of a single ureter.A molecular cascade including WNT–β-catenin signalling induces nephron formation in the metanephric mesenchyme surrounding the ureter.Patterning of the nephron along the proximal–distal axis is controlled by transcription factors such as the Wilms tumour transcription factor (WT1) and Iroquois-class homeodomain proteins (IRX3), as well as signalling pathways such as the Notch–Delta pathway.Wilms tumours are developmental tumours that can be caused by mutations in WT1 or WTX. New evidence suggests that the formation of Wilms tumours is tightly linked to abnormal β-catenin signalling.The complex development of the kidney is achieved through multifunctional proteins and the combinatorial use of transcription factors to activate or repress genes in a specific cell type.