Nephrogenesis and the renal renin-angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation

Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesised that induction of IUGR during late gestation alters the RAS and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on (a) nephron number, (b) mRNA expression of angiotensin AT1 and AT2 receptors, angiotensinogen and renin genes in the kidney, and (c) the size of maculae densae. .IUGR was induced in fetal sheep (n=7) by umbilical-placental embolization (UPE) from 110-130d of the 147d gestation; saline-infused fetuses served as controls (n=7). Samples of cortex from the left kidney were frozen and the right kidney perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT1, AT2 receptors, angiotensinogen and renin in the renal cortex were determined. In IUGR fetuses at 130d, body and kidney weights were significantly reduced and nephron number was reduced by 24 . There was no difference in renin, angiotensinogen or AT1 and AT2 receptor mRNA expression levels in the IUGR kidneys compared to controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment, but does not affect renal corpuscle or macula densa size, or renal RAS gene expression. Key words: IUGR, nephron endowment, kidney, macula densa, stereology.