Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS.
Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS.
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在脓毒症模型中，肾脏产生的精氨酸受到损害：LPS 后的早期事件。
DOI：
10.1152/ajpregu.00373.2004
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Munger,KarenA
中科院分区：
文献类型：
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作者：
Lortie,MarkJ;Satriano,Joseph;Gabbai,FrancisB;Thareau,Sonia;Khang,Ser;Deng,Aihua;Pizzo,DonaldP;Thomson,ScottC;Blantz,RolandC;Munger,KarenA
脂多糖 (LPS) 在实验中用于引发在人类脓毒症中观察到的先天生理反应。我们之前已经表明，LPS 在诱导型一氧化氮合酶 (iNOS) 活性之前导致血浆精氨酸耗尽，这表明精氨酸摄取和/或产生的变化而不是消耗的增加是造成这种情况的原因。由于肾脏是循环精氨酸的主要来源，而肾功能衰竭是败血症的标志，因此我们确定了精氨酸代谢和肾功能相对于 iNOS 表达的变化的时间过程。静脉注射 LPS 给麻醉大鼠 120 分钟后，导致平均动脉血压下降，同时肺和肝脏中血浆一氧化氮终产物 (NOx) 和 iNOS 表达增加。有趣的是，肾功能受损先于 iNOS 活性 30-60 分钟，并且与肾精氨酸产生减少同时发生。肾精氨酸产生的基线率为~60 μmol·h−1·kg−1，对应于~20分钟的表观血浆半衰期，并且在LPS的60分钟内减少了一半。基于全身产生和清除的计算表明，通常只有 5% 的肾脏精氨酸输出注定会变成一氧化氮，并且 <25% 的 LPS 受损的肾脏产生在前 4 小时内转化为 NOx。此外，我们提供了新的观察结果，表明肾脏似乎对 LPS 诱导的 iNOS 难以抵抗，因为在 4 小时内肾脏 NOx 产生没有发生明显的增强，并且与肝脏或肺中的 iNOS 表达相比，肾脏中的 iNOS 表达减弱。这些研究表明，LPS 后细胞外精氨酸含量迅速下降的主要因素是肾脏产生受损，这种现象似乎与肾灌注减少有关。
Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis. We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible. Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression. LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver. Interestingly, impairment of renal function preceded iNOS activity by 30–60 min and occurred in tandem with decreased renal arginine production. The baseline rate of renal arginine production was ∼60 μmol·h−1·kg−1, corresponding to an apparent plasma half-life of ∼20 min, and decreased by one-half within 60 min of LPS. Calculations based on the systemic production and clearance show that normally only 5% of kidney arginine output is destined to become nitric oxide and that <25% of LPS-impaired renal production was converted to NOx in the first 4 h. In addition, we provide novel observations indicating that the kidney appears refractory to iNOS induction by LPS because no discernible enhancement of renal NOx production occurred within 4 h, and iNOS expression in the kidney was muted compared with that in liver or lung. These studies demonstrate that the major factor responsible for the rapid decrease in extracellular arginine content following LPS is impaired production by the kidney, a phenomenon that appears linked to reduced renal perfusion.