Di Paolo Salvatore, Monno Raffaella, Stallone Giovanni, Grandaliano Giuseppe, Schena Antonio, Greco Pantaleo, Volpe Paolo, Resta Leonardo, Selvaggi Luigi, Schena F Paolo, Gesualdo Loreto
Department of Emergency and Organ Transplant, Division of Nephrology, University of Bari, Policlinico, Baria, Italy.
Am J Kidney Dis. 2002 Apr;39(4):776-83. doi: 10.1053/ajkd.2002.31998.
Endothelin-1 (ET-1) and nitric oxide (NO) have been suggested to have a focal role in the regulation of placental and fetal growth. Cyclosporine A (CsA) has been shown to strongly modulate ET-1 and NO synthesis and thus has the potential to affect fetal growth and maternal state. Eleven CsA-treated female kidney transplant recipients were recruited. Fourteen healthy pregnant women served as controls. Placental expression of ET-1 and tissue factor (TF) was evaluated by in situ hybridization, and NO synthase (NOS) was evaluated by staining with the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase and in situ hybridization. Kidney transplant recipients showed a marked reduction in NADPH-diaphorase staining, as well as endothelial constitutive NOS (ecNOS) messenger RNA, whereas inducible NOS expression was unchanged. Normal placenta showed a strong positive ET-1 signal along the endothelium of uteroplacental arteries within the basal plate, which increased markedly in decidua of transplant recipients. Thus, transplant recipients showed a remarkable alteration in ET-1/ecNOS balance without alteration in fetal growth or maternal renal function. Next, we explored the state of placental endothelial cell activation downstream from vasoactive factors by evaluating TF gene expression. Transplant recipients did not show modification of TF transcript compared with healthy pregnant women. CsA potently affected the placental ET-1/ecNOS vasoactive balance. Nevertheless, newborns from transplant recipient mothers were appropriate for gestational age, and transplant recipients did not show systemic hypertension or impending renal damage. It is suggested that CsA may blunt the activation of endothelial cells and priming of endothelial-derived substances, which possibly lie downstream from the cited vasoactive agents.
内皮素-1（ET-1）和一氧化氮（NO）被认为在胎盘和胎儿生长调节中起关键作用。环孢素A（CsA）已被证明能强烈调节ET-1和NO的合成，因此有可能影响胎儿生长和母体状态。招募了11名接受CsA治疗的女性肾移植受者。14名健康孕妇作为对照。通过原位杂交评估ET-1和组织因子（TF）的胎盘表达，通过用还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）-黄递酶染色和原位杂交评估一氧化氮合酶（NOS）。肾移植受者的NADPH-黄递酶染色以及内皮型组成型NOS（ecNOS）信使核糖核酸显著减少，而诱导型NOS表达未改变。正常胎盘在基底板内子宫胎盘动脉内皮沿线显示强烈的ET-1阳性信号，在移植受者的蜕膜中显著增加。因此，移植受者的ET-1/ecNOS平衡发生了显著改变，但胎儿生长或母体肾功能未改变。接下来，我们通过评估TF基因表达来探讨血管活性因子下游胎盘内皮细胞的激活状态。与健康孕妇相比，移植受者未显示TF转录本的改变。CsA强烈影响胎盘ET-1/ecNOS血管活性平衡。然而，移植受者母亲的新生儿孕周合适，移植受者未出现系统性高血压或即将发生的肾损害。提示CsA可能抑制内皮细胞的激活和内皮衍生物质的启动，这可能位于上述血管活性因子的下游。
