Duong Van Huyen Jean-Paul, Viltard Mélanie, Nehiri Touria, Freund Nicole, Bélair Marie-France, Martinerie Cécile, Lelongt Brigitte, Bruneval Patrick, Lelièvre-Pégorier Martine
INSERM U652, IFR 58, Centre de recherche des Cordeliers, Université René Descartes (Paris 5), Paris, France.
Lab Invest. 2007 Jul;87(7):680-9. doi: 10.1038/labinvest.3700562. Epub 2007 May 14.
Remodeling of extracellular matrix (ECM) is an important physiological feature of normal growth and development. Recent studies have emphasized the role of matrix metalloproteinases (MMP-2 and MMP-9) in normal mouse nephrogenesis. We have demonstrated previously in the rat that in utero exposure to maternal diabetes impairs renal development leading to a 30% reduction in the nephron number. Transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) are known to mediate high glucose effects on matrix degradation. The aim of the present study was to address the expression of type IV collagenase and TGF-beta1/CTGF systems in rat kidney during normal development and after in utero exposure to maternal diabetes. Both MMP-2 and MMP-9 mRNA metanephric expressions and activities were dramatically downregulated in kidneys issued from diabetic fetuses and in metanephros cultured in the presence of high glucose concentration. TGF-beta1 and CTGF expressions were significantly enhanced in diabetic fetal kidneys and in high glucose cultured metanephroi. Conditioned media obtained from metanephroi grown with high glucose concentration upregulated functional TGF-beta activity in transfected ATDC5 cells. In conclusion, in impaired nephrogenesis resulting from in utero exposure to maternal diabetes, alteration of both type IV collagenase and TGF-beta1/CTGF systems may lead to abnormal remodeling of ECM, which may, in turn, induce defects in ureteral bud branching leading to the observed reduction in the nephron number with consequences later in life: progression of chronic renal disease and hypertension.
细胞外基质（ECM）重塑是正常生长发育的重要生理特征。最近的研究强调了基质金属蛋白酶（MMP - 2和MMP - 9）在正常小鼠肾发生中的作用。我们之前在大鼠中已经证明，子宫内暴露于母体糖尿病会损害肾脏发育，导致肾单位数量减少30%。已知转化生长因子 - β1（TGF - β1）和结缔组织生长因子（CTGF）介导高糖对基质降解的影响。本研究的目的是探讨正常发育过程中以及子宫内暴露于母体糖尿病后大鼠肾脏中IV型胶原酶和TGF - β1/CTGF系统的表达情况。在糖尿病胎儿的肾脏以及在高糖浓度下培养的后肾中，MMP - 2和MMP - 9 mRNA在后肾中的表达和活性均显著下调。TGF - β1和CTGF的表达在糖尿病胎儿肾脏和高糖培养的后肾中显著增强。从高糖浓度培养的后肾获得的条件培养基上调了转染的ATDC5细胞中的功能性TGF - β活性。总之，在子宫内暴露于母体糖尿病导致的肾发生受损中，IV型胶原酶和TGF - β1/CTGF系统的改变可能导致ECM的异常重塑，进而可能诱导输尿管芽分支缺陷，导致观察到的肾单位数量减少，并在以后的生活中产生后果：慢性肾病和高血压的进展。
