Duong Van Huyen J-P, Amri K, Bélair M-F, Vilar J, Merlet-Bénichou C, Bruneval P, Lelièvre-Pégorier M
INSERM U430, IFR 58, Hôpital Broussais, Paris, France.
Cell Tissue Res. 2003 Dec;314(3):367-79. doi: 10.1007/s00441-003-0803-4. Epub 2003 Oct 2.
Exposure to hyperglycemia in utero impairs rat nephrogenesis. The effect of maternal diabetes on insulin-like growth factors and their receptors in the fetal kidney is associated with an increase in both mRNA and protein of the insulin-like growth factor II/mannose 6-phosphate receptor. However, this receptor has never been localized in the fetal kidney. The spatial and temporal distribution of the three insulin-like growth factor receptors (insulin-like growth factor I receptor, insulin-like growth factor II/mannose 6-phosphate receptor and insulin receptor) in rat metanephros during both normal and streptozotocin-induced diabetic renal development was investigated using in situ hybridization and immunohistochemistry. All receptors were found in the fetal kidney from the start of nephrogenesis. Insulin-like growth factor I receptor expression was ubiquitous and continuously present during metanephric development. Insulin receptor expression was developmentally regulated during kidney maturation with an enhanced expression in proximal tubules at the late stages of development. Insulin-like growth factor II/mannose 6-phosphate receptor expression was ubiquitous in the early stages of development and was dramatically decreased at the late stages of normal kidney development. Insulin receptor and insulin-like growth factor I receptor expressions were unchanged in diabetic metanephroi. Although the spatial expression of insulin-like growth factor II/mannose 6-phosphate receptor was unaffected by hyperglycemia, its expression was not downregulated in the mesenchyme of the nephrogenic zone of diabetic fetuses on gestational day 20. This study suggests a crucial role of insulin-like growth factor II/mannose 6-phosphate receptor in the pathogenesis of the impaired nephrogenesis in fetuses of diabetic mothers.
子宫内暴露于高血糖会损害大鼠肾发生。母体糖尿病对胎儿肾脏中胰岛素样生长因子及其受体的影响与胰岛素样生长因子II/甘露糖6-磷酸受体的mRNA和蛋白质增加有关。然而，该受体从未在胎儿肾脏中定位过。使用原位杂交和免疫组织化学研究了正常和链脲佐菌素诱导的糖尿病肾脏发育过程中大鼠后肾中三种胰岛素样生长因子受体（胰岛素样生长因子I受体、胰岛素样生长因子II/甘露糖6-磷酸受体和胰岛素受体）的时空分布。从肾发生开始，所有受体均在胎儿肾脏中被发现。胰岛素样生长因子I受体表达普遍存在，在后肾发育过程中持续存在。胰岛素受体表达在肾脏成熟过程中受到发育调节，在发育后期近端小管中表达增强。胰岛素样生长因子II/甘露糖6-磷酸受体表达在发育早期普遍存在，在正常肾脏发育后期显著降低。糖尿病后肾中胰岛素受体和胰岛素样生长因子I受体表达未改变。虽然胰岛素样生长因子II/甘露糖6-磷酸受体的空间表达不受高血糖影响，但其在妊娠第20天糖尿病胎儿肾发生区间充质中的表达未下调。本研究提示胰岛素样生长因子II/甘露糖6-磷酸受体在糖尿病母亲胎儿肾发生受损的发病机制中起关键作用。
