Perinatal nephron programming is not so sweet in maternal diabetes.

Development of the permanent, metanephric kidney begins at approximately embryonic day 11 (E11) in mice, E12 in rats, and during the fourth through fifth gestational weeks in humans. During these stages, the ureteric bud projects from the mesonephric duct and enters the metanephric anlage, whereupon buds branch repeatedly and ultimately form the collecting duct system of the mature kidney (and urothelium, including the renal pelvis, ureters, and bladder trigone). At the inception of nephrogenesis, metanephric mesenchymal cells are attracted to and condense around each tip of an advancing ureteric bud branch. Shortly after condensation, the mesenchyme then converts to polarized epithelia, which proceeds through an orderly sequence of nephric structures (termed vesicle, commaand s-shaped, developing capillary loop, and glomerular stages) that eventually constitute the mature nephron. These nephrogenic processes of ureteric bud growth and branching, mesenchymal cell induction and aggregation, conversion to epithelia, and glomerular differentiation and tubule elongation occur repeatedly until there is a full complement of nephrons. Nephrogenesis concludes approximately 1 wk after birth in rodents and during the 34th gestational week in humans. Considerable progress has been made in understanding many of the molecular details that underlie the induction of nephrogenesis, and only a few of them can be mentioned here. For example, the “paired box” transcription factor-2 (Pax2) first appears during the caudal descent of the nephric duct, then expresses in uninduced and induced metanephric mesenchyme, where it stimulates expression of glial cell– derived neurotrophic factor,1 and also expresses in ureteric bud epithelia, where it suppresses apoptosis. Pax2 also increases expression of Wnt-4, a secreted glycoprotein that activates the -catenin signaling pathway regulating cell growth.2 The transcription factor WT1 is expressed in uninduced mesenchyme but is sharply upregulated as cells condense around ureteric bud branches. Wnt-4 is also upregulated in condensing mesenchyme and, together with WT1, expresses through the vesicle and commaand S-shaped stages, suggesting both of these proteins are key mediators of epithelial differentiation. One of the gene products directly regulated by WT1 is Pax2, which becomes downregulated during s-shaped stages of nephron development.3 Similarly, reciprocal expression of the receptor tyrosine kinase Ret and its ligand, glial cell– derived neurotrophic factor, by ureteric bud epithelia and metanephric mesenchyme, respectively, induces and maintains ureteric bud branching morphogenesis.1 As the condensed metanephric mesenchymal cells serially convert to epithelia, the expression of a host of mesenchymal proteins (e.g., neural cell adhesion molecule, vimentin, types I and III collagen) are suppressed, whereas proteins that typify epithelia (E-cadherin, cytokeratin, type IV collagen, and laminin) all upregulate. Although much has been learned about the induction of nephrogenesis, considerably less is known about mechanisms that conclude the process. Nevertheless, many factors contribute to final nephron endowment, including the extent of ureteric bud elongation and branching, conversion of mesenchyme to epithelia, maintenance of the epithelial nephric figures, and overall rates of metanephric mitosis and apoptosis; some of the genetic regulators of these processes have already been summarized. Furthermore, unbiased stereologic methods show mature human kidney can average from as few as approximately 200,000 to nearly 2 million nephrons.4 This wide variation in nephron endowment may have profound consequences, however, and there is increasing evidence that individuals with reduced nephron number are prone to develop hypertension, renal failure, and/or other cardiovascular disorders later in life. Notably, mice with a complete absence of Pax2 lack the caudal portion of the Wolffian duct, from which the ureteric bud originates, and are therefore anephric.5 Humans who are heterozygous for Pax2 mutations have renalcoloboma syndrome, which results in ocular colobomas, renal hypoplasia, and renal failure in childhood.6 Additional evidence shows heterozygous mutations of Pax2 in mice also result in loss of renal mass with increased apoptosis and decreased branching of the ureteric bud, leading to significantly fewer nephrons.6 Several different genetic mutations cause renal growth disorders,7,8 but there are also many important—and possibly much more prevalent—environmental causes. A growing body of data in humans and experimental animals indicates that maternal malnutrition, placental insufficiency, fetal exposure to certain medications and other toxins, inhibition of the renin-angiotensin system, and/or vitamin A (retinoid) depletion all can result in low birth weight.9 Although this may not always affect nephron endowment, in many cases low birth weight correlates inversely with a tendency for the development of hypertension, proteinuria, and metabolic syndrome in adulthood.9 Increasingly, the Barker hypothesis (adult disease has fetal origins), as it relates to certain renal functional abnormalities in maturity, attributes at least some of the harm to events taking place specifically during kidney organogenesis, which in humans normally occurs exclusively in utero. Maternal hyperglycemia can similarly induce a wide range of developmental abnormalities affecting multiple organ systems in the fetus (diabetic embryopathy), including kidney.10,11 Indeed, women with pregestational diabetes and fasting hyperglycemia Published online ahead of print. Publication date available at www.jasn.org.