Altered Nephrogenesis Due to Maternal Diabetes Is Associated With Increased Expression of IGF-II/Mannose-6-Phosphate Receptor in the Fetal Kidney

Altered Nephrogenesis Due to Maternal Diabetes Is Associated With Increased Expression of IGF-II/Mannose-6-Phosphate Receptor in the Fetal Kidney Kaouthar Amri 1 , Nicole Freund 1 , J.P. Duong Van Huyen 2 , Claudie Merlet-Bénichou 1 and Martine Lelièvre-Pégorier 1 1 INSERM U 319, Université Paris 7 Denis-Diderot, and 2 INSERM U430, Hôpital Broussais, Paris, France Abstract We have recently demonstrated that the exposure to hyperglycemia in utero impairs nephrogenesis in rat fetuses (Amri K et al., Diabetes 48:2240–2245, 1999). Diabetic pregnancy is commonly associated with alterations in the IGF system in fetal tissues. It has also been shown that both IGF-I and IGF-II are produced within developing metanephros and promote renal organogenesis. Therefore, we investigated the effect of maternal diabetes on IGFs and their receptors in developing fetal rat kidney. Diabetes was induced in pregnant rats by a single injection of streptozotocin on day 0 of gestation. We measured the amounts of IGF and their receptors, both proteins and mRNAs, in the metanephroi of fetuses issued from diabetic subjects and in age-matched fetuses from control subjects (14–20 days of gestation). IGF-II was produced throughout fetal nephrogenesis, whereas IGF-I protein was not detected, suggesting a critical role of IGF-II in kidney development. Fetal exposure to maternal diabetes caused no change in IGF production in the early stages of nephrogenesis. Similarly, the amounts of IGF-I receptor and insulin receptor were not altered. By contrast, there was an increase in production of IGF-II/mannose-6-phosphate receptor throughout nephrogenesis. Because this receptor plays an essential role in regulating the action of IGF-II, the altered nephrogenesis in fetuses exposed to maternal diabetes may be linked to a decrease in IGF-II bioavailability. Footnotes Address correspondence and reprint requests to Dr. Martine Lelièvre-Pégorier, INSERM U319, Université Paris 7, 2 Place Jussieu, 75251 Paris Cedex 05, France. E-mail: pegorier{at}paris7.jussieu.fr . Received for publication 8 August 2000 and accepted in revised form 16 January 2001. IGF-IR, IGF-I receptor; IR, insulin receptor; M6PR, mannose-6-phosphate receptor; STZ, streptozotocin; TBST, Tris-buffered saline with Tween.