MILD VITAMIN-A-DEFICIENCY LEADS TO INBORN NEPHRON DEFICIT IN THE RAT

Background. Vitamin A plays a critical role in fetal organogenesis, an d its severe deficiency during pregnancy is known to result in malform ations of several organs, including the kidney. However, the consequen ces of mild vitamin A deficiency (VAD) has received little attention. In the present study, we examined the effect of in utero exposure to m ild VAD on renal organogenesis. Methods. A rat model of mild VAD compa tible with normal gestation was developed. Plasma retinol was determin ed by reverse phase HPLC in mothers and fetuses. Nephron counting was performed in kidneys of fetuses and pups issued from control and VAD m others. Metanephroi explanted from 14-day-old fetuses from both groups were cultured in the presence or absence of retinoic acid (RA), and g rowth and differentiation were assessed, c-ret expression was analyzed from fetuses exposed in utero to VAD or to normal vitamin A status an d also in meta-nephroi grown in culture with or without RA using RT-PC R. Results. The 50% reduction in circulating vitamin A levels induced by vitamin A deprivation in pregnant rats did not affect the overall f etal development. However, the number of nephrons was reduced by 20% i n 21-day-old VAD fetuses. The number of nephrons was closely correlate d with circulating Vitamin A level in both VAD and control fetuses. Me tanephroi taken from VAD fetuses developed to a lesser extent in vitro , but their capacity to respond to exogenous retinoic acid was not alt ered. Finally, we found that the expression of the proto-oncogene c-re t was modulated according to the retinoid environment. Conclusion. We conclude that vitamin A supply to the fetus is critical in determining the number of nephrons. Data available thus far on the frequency of m ild VAD during pregnancy and on the long-term consequences of inborn n ephron deficit highlight the clinical relevance of the present study.