Control of renal haemodynamics in the developing kidney - implications for fetal programming

Renal blood flow and micropuncture studies were conducted in late gestationfetal sheep (gestational age 134 - 141 days; term 150 days) and neonatal lambs (8 -18 days after birth) to study the forces involved in glomerular filtration (GFR)and characterize the tubuloglomerular feedback (TGF) system duringdevelopment. These studies required the kidney to be immobilized so stablemodels in acutely prepared anaesthetized animals were developed. Fetuses werestudied in a heated water bath exteriorized from the uterus but with an intactumbilical circulation.The lower GFR in fetuses than lambs was found to be due to both lower netfiltration pressures (P<0.001) and a lower ultrafiltration coefficient (P<0.001). TGFwas present at both ages, but in fetuses the sensitivity was higher (P<0.001) andreactivity was lower (P<0.001). The reduction in TGF sensitivity between fetaland neonatal life may facilitate the increase in renal blood flow and GFR whichoccurs at this time.In both fetuses and lambs the sensitivity of the TGF curve was reduced byvolume expansion (P<0.001, P<0.05) and reactivity was reduced in lambs(P<0.001). Furosemide abolished TGF at both ages. In both fetuses and lambs,TGF reactivity was increased by inhibition of neuronal nitric oxide synthase(nNOS; P<0.01, P<0.001) and in lambs, TGF sensitivity was increased (P<0.01).This indicates that nitric oxide produced by the macula densa modulates TGFduring development.In offspring destined to become hypertensive due to maternal dexamethasonetreatment in early gestation TGF sensitivity tended to be enhanced in fetal lifeand was enhanced in lambs (P<0.01). Increased TGF sensitivity may contribute tothe development of hypertension in this model of developmental programming.The effects of nNOS inhibition were attenuated in these animals, suggesting thatthey have low tonic production of nitric oxide by the macula densa.In fetuses whose mothers had been subtotally nephrectomized prior to mating toinduce maternal mild renal impairment, GFR was increased (P<0.01) but netfiltration pressure was reduced (P<0.001) so the ultrafiltration coefficient wasincreased (P