Understanding the role of maternal diet on kidney development; an opportunity to improve cardiovascular and renal health for future generations

Abstract

The leading causes of mortality and morbidity worldwide are cardiovascular disease (high blood pressure, high cholesterol and renal disease), cancer and diabetes. It is increasingly obvious that the development of these diseases encompasses complex interactions between adult lifestyle and genetic predisposition. Maternal malnutrition can influence the fetal and early life environment and pose a risk factor for the future development of adult diseases, most likely due to impaired organogenesis in the developing offspring. This then predisposes these offspring to cardiovascular disease and renal dysfunction in adulthood. Studies in experimental animals have further illustrated the significant impact maternal diet has on offspring health. Many studies report changes in kidney structure (a reduction in the number of nephrons in the kidney) in offspring of protein-deprived dams. Although the early studies suggested that increased blood pressure was also present in offspring of protein-restricted dams, this is not a universal finding and requires clarification. Importantly, to date, the literature offers little to no understanding of when in development these changes in kidney development occur, nor are the cellular and molecular mechanisms that drive these changes well characterised. Moreover, the mechanisms linking maternal nutrition and a suboptimal renal phenotype in offspring are yet to be discerned-one potential mechanism involves epigenetics. This review will focus on recent information on potential mechanisms by which maternal nutrition (focusing on malnutrition due to protein restriction, micronutrient restriction and excessive fat intake) influences kidney development and thereby function in later life.

Figure 1

Kidney development. The mammalian kidney develops through three stages (pronephros, mesonephros and metanephros). The pronephros develops from the nephric duct, following which, mesonephric development occurs in conjunction with the degeneration of the pronephros and the formation of the mesonephric tubules. The metanephros develops from the induction of the metanepheric mesenchyme by the ureteric bud from the nephric (Wolffian) duct. As the ureteric bud branches into the metanephric mesenchyme, the mesenchyme around the tips of this branching structure are induced to form renal vesicles. Renal vesicles will progress through the comma-shaped body and S-shaped body stages before connecting to the collecting system of the developing kidney to form a developed nephron.

Figure 2

Molecular control of early kidney development. Early development of the metanephros, the permanent mammalian kidney, is under tight molecular control. Outgrowth and branching morphogenesis of the ureteric bud is controlled by the expression of receptors Gfrα1 and C-ret to which Gdnf binds. Production of Gdnf is under the influence of Pax2, Together these factors stimulate branching morphogenesis of the kidney. Bmp4 inhibits lateral branching of the ureteric, which ensures tight control of branching morphogenesis. Induction of the metanephric mesenchyme to undergo epithelial to mesenchymal transition is influenced by Wnt4 and Hnf4α. The formation of renal vesicles (from the cap mesenchyme) is controlled by the number of Six2 positive cells (denoting renal stem cells). Once committed to forming a nephron, these cells begin to express Pax2, Wnt4 and Hnf4α.