Developmental Programming of Glomerular Podocyte Endowment

Abstract

A range of perturbations to the maternal environment result in low nephron endowment in offspring, which is often linked to increased blood pressure and renal pathology in later life. Given that nephrogenesis in mammals ends shortly before or after birth, this nephron deficit is permanent. To date, very few studies have examined the morphology of nephrons in offspring born with low nephron endowment. Given the link between podocyte loss and glomerulosclerosis in adults, we examined whether maternal perturbations also result in low podocyte endowment in offspring, thereby rendering offspring at increased risk of adult disease. Three models of maternal perturbation were investigated: (1) gestational hypoxia in mice; (2) maternal low protein diet (LPD) in mice followed by postnatal hyperglycaemia; and (3) maternal low protein diet in rats followed by high fat feeding. Podocytes were counted at postnatal day 21 in whole glomeruli contained in tissue slices immunostained for specific podocyte markers, cleared and imaged with confocal microscopy. In all three models, total podocyte number per glomerulus was reduced in settings of maternal perturbation. In male mice exposed to hypoxia, podocyte endowment was 15% lower than controls (p<0.01), but no effect was observed in females; in male and female mouse LPD offspring, podocyte endowment was 15% (p<0.001) and 9% (p<0.05) lower than controls; and in male LPD rats (females were not studied), podocyte endowment was 15% (p<0.0001) lower than controls. This is the first report of developmental programming of low podocyte endowment. We have identified low podocyte endowment in two species, three models and both sexes. We are currently investigating whether this podocyte deficit is permanent, and the effects on renal function in later life.