Wang Wei, Zolty Einath, Falk Sandor, Summer Sandra, Zhou Zhu, Gengaro Patricia, Faubel Sarah, Alp Nicholas, Channon Keith, Schrier Robert
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262-0001, USA.
Am J Physiol Renal Physiol. 2008 Mar;294(3):F571-6. doi: 10.1152/ajprenal.00538.2007. Epub 2008 Jan 2.
Endotoxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and renin-angiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia.
内毒素相关的急性肾损伤已被证明能显著诱导一氧化氮（NO），其激活交感神经和肾素 - 血管紧张素系统，导致肾血管收缩。虽然已知血管平滑肌细胞会上调诱导型一氧化氮合酶（iNOS），但对于内毒素血症期间作为NO来源的内皮细胞了解较少。因此，我们在体外对小鼠微血管内皮细胞以及在体内对内皮型GTP环水解酶（四氢生物蝶呤的限速酶，四氢生物蝶呤是一氧化氮合酶的一种辅助因子）过表达的转基因小鼠进行了研究。脂多糖（LPS）显著诱导内皮细胞iNOS表达以及培养基中的NO浓度，而内皮型一氧化氮合酶的表达没有变化。与野生型（WT）小鼠相比，GTP环水解酶 - 1转基因（Tg）小鼠经LPS处理后，基线尿NO与肌酐比值显著增加，肾iNOS表达和血清NO水平增加更显著。给予1.0mg/kg LPS时，Tg小鼠的肾小球滤过率和肾血流量显著降低，而相同剂量LPS处理的WT小鼠未观察到变化。在内毒素血症期间，Tg小鼠的血清IL - 6水平显著高于WT小鼠。抗氧化剂tempol改善了Tg小鼠的肾小球滤过率。因此，在内毒素血症期间，内皮细胞可能是iNOS和血清NO浓度的重要来源，从而增加了对急性肾损伤的易感性。活性氧似乎参与了内毒素血症期间Tg小鼠的这种急性肾损伤。
