Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep
Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep
复制标题
绵羊先天性肾质量减少后，肾功能障碍与一氧化氮贡献减少和血管收缩增强有关
作者：
Y. Lankadeva;Reetu R. Singh;K. Moritz;H. Parkington;K. Denton;M. Tare
背景-出生时先天性肾质量减少的儿童在成年后患高血压和慢性肾脏疾病的风险增加，尽管其机制尚不清楚。羊胎儿单肾切除术（uni-x）后也会出现类似的后遗症，导致30%的肾单位缺损。我们假设，肾功能不全是由一氧化氮（NO）和血管功能障碍的uni-x羊的贡献减少。方法和结果：在5岁雌性unix和假手术绵羊中，在NO抑制（N -硝基-L-精氨酸甲酯[L-NAME]）之前和期间测量平均动脉压、肾小球滤过率和肾血流量。在阻力动脉中评估反应性，包括肾叶动脉和弓形动脉。uni-x动物的基础平均动脉压升高15 mm Hg，肾小球滤过率和肾血流量降低约30%（P<0.001）。L-NAME使两组的平均动脉压均升高1.17 mm Hg，而unix绵羊的肾小球滤过率和肾血流量降低较少（P <0.01）。uni-x绵羊肾皮质内皮型NO合酶和Ser-1177磷酸化内皮型NO合酶蛋白水平显著升高（P<0.05）。uni-x绵羊的叶动脉对苯肾上腺素和硝基酪氨酸染色的反应性增强，对内皮刺激的敏感性降低。在uni-x绵羊的叶动脉中，血管扩张剂前列腺素类对内皮依赖性舒张的贡献减少，伴随着环氧合酶-1和-2基因表达的减少（P<0.05）。unix绵羊肾动脉神经血管收缩增强1.5倍（P<0.05）。结论：先天性肾质量减少后的肾功能不全与NO对肾血流动力学的调节受损有关。肾血流量和肾小球滤过率的降低是由基础NO贡献受损、内皮功能障碍和血管对交感神经刺激的反应性增强所支持的。
Background— Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep. Methods and Results— In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (N&ohgr;-nitro-L-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (P<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (PInteraction<0.01). Endothelial NO synthase and Ser-1177–phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep (P<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression (P<0.05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep (P<0.05). Conclusions— Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
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DOI：
10.1681/asn.v16875
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期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
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期刊：
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影响因子：
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DOI：
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发表时间：
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期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
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作者：
Roghair,RobertD;Volk,KennethA;Lamb,FredS;Segar,JeffreyL
通讯作者：
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