The nephron number counts--from womb to tomb.

Nephron number is known to correlate directly with renal prognosis [1]. The number of nephrons is the result of nephron endowment during embryonic development and the loss of nephrons in later life. Nephron endowment is determined by embryonic conditions during renal development and genetic factors [2, 3]. In later life, mechanic, toxic, ischaemic and inflammatory insults can cause nephron damage and loss. In addition, nephron damage and loss can also result from persistent hyperfiltration as a result of an insufficient number of nephrons due to low nephron endowment or acquired nephron loss [4, 5]. The latter illustrates the intricate interrelationship between nephron number and nephron damage. Intrauterine growth restriction (IUGR) is a wellknown model for decreased nephron endowment [6, 7]. In this issue of NDT, Dr Menendez-Castro et al. [8] speculate that IUGR not only renders the kidney more susceptible to injury because of low nephron endowment, but also due to fetal programing of the Wilms Tumour suppressor gene (Wt1). During renal development, the kidney is formed by the interaction of two mesodermal-derived structures: the metanephric mesenchyme (MM) and the tubular ureteric bud (UB). By reciprocal interaction, the MM induces the UB to grow and branch, whereas the UB induces the MM to subsequently form the pre-tubular aggregate which undergoes mesenchymal-epithelial transition and subsequently forms the immature stages of the nephron. These nephrons finally become vascularized by the invasion of angioblasts forming the glomerulus and peritubular capillaries. The UB gives rise to the collecting duct and the urinary collection system, whereas the MM gives rise to the rest of the different nephron segments. Nephrogenesis ceases because of lack of replacement of non-induced MM at gestational week 32 in humans and within the 10 days after birth in mice and rats [9]. After nephrogenesis has ceased, renal function still increases by haemodynamic changes and nephron hypertrophy (loadthen-grow strategy) [10]. Nephrons lost after cessation of nephrogenesis are not replaced. Although the exact mechanisms involved in the cessation of nephrogenesis are unknown, the final burst of nephrogenesis shortly after birth in mice appears to exhaust the progenitors in the cap of the MM in association with an increase in oxygenation that shifts progenitor activity from renewal to differentiation [11, 12]. In this context, it is of note that in contrast to the postnatal situation, prenatal unilateral nephrectomy induced extended nephrogenesis in the contralateral kidney [13]. Finally, (maternal) dietary protein intake and specific amino acids might also be involved in the regulation of nephron endowment (see below) [14]. The Wilms tumour suppressor gene Wt1 plays a critical role in the regulation of early nephron formation by forcing the proliferating pluripotent MM cells to differentiate and exit the undifferentiated cell cycle [15]. Wt1 encodes a protein with four C-terminal Cys2-His2 Zn fingers of the Krüppel type [15]. A combination of alternative splicing, alternative translation sites and RNA editing leads to the expression of at least 24 different isoforms of Wt1. Of particular interest are two alternative splice donor sites at the end of exon 9 causing the inor exclusion of three amino acids, lysine threonine serine (abbreviated as KTS) between Zn fingers 3 and 4 (designated as +KTS and −KTS). Different functions have been described for the different isoforms of Wt1 and the ratio of +KTS/−KTS is tightly regulated. During nephrogenesis, Wt1 is expressed immediately after induction of the MM, and its expression becomes progressively restricted to the podocytes and parietal epithelial cells of Bowman’s capsule [16–18]. The latter cells have recently been demonstrated to contain the podocyte progenitor cell population [19]. During nephrogenesis, Wt1 expression downregulates the genes involved in proliferation and the maintenance of non-induced MM-like six2, and induces the genes involved in podocytic differentiation (e.g.