Department of Nephrology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.
Am J Physiol Renal Physiol. 2012 Aug 1;303(3):F396-404. doi: 10.1152/ajprenal.00488.2011. Epub 2012 May 2.
Pregnancy worsens renal function in females with chronic renal failure (CRF) through an unknown mechanism. Reduced nitric oxide (NO) generation induces renal injury. Arginine transport by cationic amino acid transporter-1 (CAT-1), which governs endothelial NO generation, is reduced in both renal failure and pregnancy. We hypothesize that attenuated maternal glomerular arginine transport promotes renal damage in CRF pregnant rats. In uremic rats, pregnancy induced a significant decrease in glomerular arginine transport and cGMP generation (a measure of NO production) compared with CRF or pregnancy alone and these effects were prevented by l-arginine. While CAT-1 abundance was unchanged in all experimental groups, protein kinase C (PKC)-α, phosphorylated PKC-α (CAT-1 inhibitor), and phosphorylated CAT-1 were significantly augmented in CRF, pregnant, and pregnant CRF animals; phenomena that were prevented by coadministrating l-arginine. α-Tocopherol (PKC inhibitor) significantly increased arginine transport in both pregnant and CRF pregnant rats, effects that were attenuated by ex vivo incubation of glomeruli with PMA (a PKC stimulant). Renal histology revealed no differences between all experimental groups. Inulin and p-aminohippurate clearances failed to augment and renal cortical expression of hypoxia inducible factor-1α (HIF-1α) significantly increased in CRF pregnant rat, findings that were prevented by arginine. These studies suggest that in CRF rats, pregnancy induces a profound decrease in glomerular arginine transport, through posttranslational regulation of CAT-1 by PKC-α, resulting in attenuated NO generation. These events provoke renal damage manifested by upregulation of renal HIF-1α and loss of the ability to increase glomerular filtration rate during gestation.
妊娠通过未知机制使慢性肾衰竭（CRF）女性的肾功能恶化。一氧化氮（NO）生成减少可导致肾损伤。阳离子氨基酸转运蛋白-1（CAT-1）介导的精氨酸转运，其控制内皮细胞NO生成，在肾衰竭和妊娠中均减少。我们假设，母体肾小球精氨酸转运的减弱会促进 CRF 妊娠大鼠的肾脏损伤。在尿毒症大鼠中，与 CRF 或妊娠单独相比，妊娠诱导肾小球精氨酸转运和 cGMP 生成（NO 产生的一种衡量指标）显著降低，而 l-精氨酸可预防这些作用。虽然在所有实验组中 CAT-1 丰度均无变化，但蛋白激酶 C（PKC）-α、磷酸化 PKC-α（CAT-1 抑制剂）和磷酸化 CAT-1 在 CRF、妊娠和妊娠 CRF 动物中明显增加；而 l-精氨酸共同给药可预防这些现象。α-生育酚（PKC 抑制剂）可显著增加妊娠和 CRF 妊娠大鼠的精氨酸转运，而肾小球体外孵育 PMA（PKC 刺激物）可减弱这些作用。肾组织学检查显示所有实验组之间无差异。菊粉和对氨马尿酸清除率未能增加，CRF 妊娠大鼠肾皮质缺氧诱导因子-1α（HIF-1α）表达显著增加，而精氨酸可预防这些现象。这些研究表明，在 CRF 大鼠中，妊娠通过 PKC-α对 CAT-1 的翻译后调节，诱导肾小球精氨酸转运明显减少，导致 NO 生成减少。这些事件引发肾脏损伤，表现为肾 HIF-1α 上调和妊娠期间肾小球滤过率增加能力丧失。
