To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

中文翻译：

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肾储备受损通过犬尿氨酸和可溶性 fms 样酪氨酸激酶 1 通路导致先兆子痫

为了解肾脏捐赠如何导致先兆子痫的风险增加，我们研究了先前进行过单肾切除术的怀孕远交小鼠，并将它们与携带双肾的假手术同窝小鼠进行了比较。在怀孕期间，未切除肾 (UNx) 的小鼠未能实现肾小球滤过率的生理性增加，并且在妊娠晚期出现高血压、白蛋白尿、肾小球内皮损伤和可溶性 fms 样酪氨酸激酶 1 (sFLT1) 的胎盘过量产生，这是一种抗血管生成药物与先兆子痫发病机制有关的蛋白质。UNx 小鼠的母体高血压与低血浆容量、胎儿再吸收率增加、螺旋动脉重塑受损和胎盘缺血有关。为了评估潜在的机制，与同一动物的孕前浓度相比，l-犬尿氨酸是l-色氨酸的一种代谢物，在怀孕期间上调了大约 3 倍，这与之前的报告一致，表明l-犬尿氨酸在胎盘健康中具有保护作用。然而，UNx 小鼠在怀孕期间未能表现出l -犬尿氨酸的上调；此外，当 UNx 小鼠在整个怀孕期间在饮用水中喂食l-犬尿氨酸时，它们的先兆子痫样状态得到挽救，包括胎盘缺血的逆转和 sFLT1 水平的正常化。总的来说，我们为肾脏储备受损以及由此导致的上调失败提供了一个机制基础妊娠期犬尿氨酸可导致胎盘受损、胎盘灌注不足、抗血管生成状态和随后的先兆子痫。