Developmental programming of renal function: nephron endowment and beyond

In the face of adversity, the fetal kidney doesn't fare well. When resources are limiting due to pregnancy complications such as placental insufficiency, maternal hypoxia, or nutrient deficiencies, kidney development is often compromised, showing signs of reduced growth, defective nephrogenesis and abnormal morphology. Meanwhile, ‘essential organs’ such as the brain and adrenals fare better, presumably in an attempt by the fetus to ensure its best chance of survival until reproductive age (Giussani, 2016). In the ensuing years, the consequences of altered renal development manifest, and the kidney's inability to function optimally can progress to abnormal sodium handling and fluid imbalance, hypertension, and eventual chronic kidney disease. Understanding how prenatal stressors can impact kidney development and long-term function has practical implications. Recognizing that prevention is a more strategic and cost-effective approach, therapeutics instituted at the proper time in development could prevent or at least minimize the damage caused by prenatal stressors, thereby reducing the burden of chronic diseases in future generations. In a more immediate context, how abnormal kidney function impacts long-term renal function can provide important information about disease risk profile, and may inform better lifestyle choices for individuals; the avoidance of excess sodium intake for instance, may be more important for adults born preterm compared to otherwise healthy adults. Perhaps not surprisingly, elucidating how developmental stressors affect kidney development is proving challenging. Mechanistically linking developmental changes to long-term adverse health outcomes is notoriously difficult because overt functional deficits often only develop in later life. Moreover, fetal responses to stressors tend to be systemic in nature, and therefore implicate multiple organ systems; that is, separating the programming effects on renal developmental per se from the influences of other programmed systems, like the heart, vasculature and endocrine function, is deceptively complex. Even within the kidney, the study of one parameter is complicated by the need to consider the breadth of changes that accompany it. A case in point is the role of reduced nephron endowment in the long-term programming of hypertension and chronic kidney disease. Since nephrons do not proliferate beyond late gestation, fewer nephrons at birth effectively means a lower complement throughout life. With time and increased demands (i.e. high-sodium diet), the increased filtration load on each nephron can lead to glomerulosclerosis and tubular dysfunction, culminating in kidney disease. However, offspring with a reduced nephron endowment do not invariably develop hypertension and renal disease. What is more, the Brenner Hypothesis doesn't explain the marked variability in nephron endowment between seemingly healthy individuals, which can vary by more than 10-fold (Bertram et al. 2011). Thus, nephron endowment must be considered in the context of concomitant developmental changes, as well as traditional genetic and environmental risk factors which predispose an individual to chronic disease. In this issue of The Journal of Physiology, Walton et al. (2018) show that the programming of kidney function by hypoxia is more complex than previously thought. In a previous study, the authors reported that prenatal hypoxia in rats causes reductions in nephron endowment in male, but not female offspring, leading to eventual glomerulosclerosis and other markers of chronic kidney disease (Walton et al. 2017). In this follow-up study, the authors show that male offspring exhibit altered collecting duct cellular make-up concomitant with decreased urine concentrating ability (Walton et al. 2018). Although the decrease in principal cell (AQP2-positive) content in the collecting duct could ultimately reflect a reduction in nephron endowment in programmed offspring, the functional changes in sodium concentrating ability under both normal and water-deprivation conditions suggest this may be attributed to qualitative differences in collecting duct structure and function, rather than nephron numbers per se. The implication is that perhaps reduced nephron endowment is insufficient, but coupled with structural and functional deficits within the kidney, these changes lead to eventual renal dysfunction. Of course, the possibility also exists that changes in collecting duct structure and function could be secondary to a reduction in nephron endowment; such are the complexities of programming work. Another intriguing finding from the study by Walton et al. implicates reduced retinoic acid (RA) signalling as a mediator of abnormal kidney development (Walton et al. 2018). RA, a bioactive derivative of vitamin A, regulates ureteric bud branching and tubule segmentation in the developing kidney, and thereby plays a critical role in establishing both nephron number and cellular make-up (Das et al. 2014). RA receptors are expressed almost exclusively within primary and intercalated cells of the collecting duct during the final stages of nephrogenesis (Wong et al. 2011) – a time at which RA signalling appears to be altered by prenatal hypoxia (Walton et al. 2018). These results suggest that impaired RA signalling may be a central mechanism that underlies both the reduced nephron endowment and impaired collecting duct function. Irrespective of whether RA turns out to be a unifying mechanism of nephron endowment and collecting duct function, this work offers tantalizing prospects for targeting RA signalling to prevent or mitigate the kidney damage caused by prenatal hypoxia. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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