Abstract：
Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wildtype mice were treated with prazosin 12 h after CLP or nitric oxide synthase 2 (NOS-2) inhibitor, 30 min before and 6 and 12 h after CLP. In vivo experiments and biochemistry assays were performed 24 h after CLP. Sepsis decreased the systemic mean arterial pressure (MAP) and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decrease in GRK2 level associated with an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400 W. Treatment of non-septic mice with an NO donor reduced GRK2 content in the kidney. Therefore, our results show that an NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.
摘要：
与体循环中发生的情况相反，败血症中保留了肾血管对血管收缩剂的反应性。我们研究了这种独特的行为是否与α1肾上腺素能受体密度有关，G蛋白偶联受体激酶2(GRK2)与一氧化氮(NO)的推定作用.通过盲肠结扎和穿孔（CLP）在雌性小鼠中诱发脓毒症。野生型小鼠在CLP或一氧化氮合酶2（NOS-2）抑制剂后12小时接受哌唑嗪治疗，CLP前30分钟和后6和12小时。CLP后24小时进行体内实验和生化测定。脓毒症降低了全身平均动脉压（MAP）和血管对去氧肾上腺素的反应性。脓毒症也减少了基础肾血流量，通过哌唑嗪治疗使其正常化。脓毒症导致与肾脏中α1肾上腺素能受体密度增加相关的GRK2水平显着降低。在NOS-2-KO小鼠或用1400W处理的小鼠中防止了肾GRK2的消失。用NO供体处理非败血症小鼠降低了肾中的GRK2含量。因此,我们的结果表明，肾脏中GRK2水平的NO依赖性降低导致正常的α1肾上腺素能受体密度的维持。保留该受体在肾脏中的密度和/或功能性以及脓毒症中的较高血管收缩剂张力导致血管收缩。因此，血管收缩介质浓度的增加以及对它们的反应的保留(甚至增加)可能有助于解释脓毒症引起的急性肾损伤.
