Vascular Dysfunction, Oxidative Stress, and Inflammation in Autosomal Dominant Polycystic Kidney Disease
Vascular Dysfunction, Oxidative Stress, and Inflammation in Autosomal Dominant Polycystic Kidney Disease
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DOI：
10.2215/cjn.05850518
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发表时间：
2018-10-08
影响因子：
9.8
通讯作者：
Chonchol, Michel
中科院分区：
文献类型：
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作者：
Nowak, Kristen L.;Wang, Wei;Chonchol, Michel
背景和目的常染色体显性遗传性多囊肾病患者的动脉硬化和血管内皮功能障碍均明显增加，甚至在病程早期肾功能未受损时也是如此。常染色体显性遗传性多囊肾病的血管功能障碍被认为与血管氧化应激和炎症有关，但缺乏直接证据。我们评估了颈动脉-股动脉脉搏波速度（动脉僵硬度）和肱动脉血流介导的扩张早期常染色体显性遗传性多囊肾病患者的血管内皮功能（eGFR ≥ 60 ml/min/1.73 m2）和有控制性高血压史的健康对照者。与生理盐水相比，在输注抗坏血酸以抑制血管氧化应激后，还评估了肱动脉血流介导的扩张。从外周静脉收集血管内皮细胞，以测量蛋白质的表达，并通过ELISA或液相色谱-串联质谱法（LC-MS）也进行了评估循环标记物。结果共研究了61例常染色体显性遗传性多囊肾病（34 +/- 9岁[平均值+/- SD]）和19例健康对照（30 +/- 5岁）。与健康对照组相比，常染色体显性遗传性多囊肾病患者的颈动脉-股动脉脉搏波速度更高（650 +/- 131 vs 562 +/- 81 cm/s; P=0.007）。常染色体显性遗传性多囊肾病患者的肱动脉血流介导的扩张率为8.2% ± 5.8%，对照组为10.8% ± 4.7%（P=0.08）。在患有常染色体显性遗传性多囊肾病的参与者中，使用抗坏血酸时，血流介导的扩张从7.7%+/- 4.5%增加到9.4%+/- 5.2%，差异为1.72（95%置信区间，0.80至2.63），而在对照组参与者中，血流介导的扩张从10.8%+/- 4.7%无显著性降低至10.6%+/-5.4%，差异为-0.20（95%置信区间，-1.24至0.84; P相互作用=0.02）。常染色体显性遗传性多囊肾病患者的NF-B内皮细胞蛋白表达更高（0.48 +/- 0.12 vs 0.41 +/- 0.10 [强度vs人脐静脉内皮细胞对照]; P=0.03）。然而，循环氧化应激标志物和生物活性脂质介质没有显着差异，根据常染色体显性遗传性多囊肾病diagnosis.Conclusions这些结果提供支持的假设，血管氧化应激和炎症发展与常染色体显性遗传性多囊肾病。
Background and objectives Both increased arterial stiffness and vascular endothelial dysfunction are evident in patients with autosomal dominant polycystic kidney disease, even early in the course of the disease when kidney function in preserved. Vascular dysfunction in autosomal dominant polycystic kidney disease is thought to be related to vascular oxidative stress and inflammation, but direct evidence is lacking.Design, setting, participants, & measurements We assessed carotid-femoral pulse-wave velocity (arterial stiffness) and brachial artery flow-mediated dilation (vascular endothelial function) in participants with early-stage autosomal dominant polycystic kidney disease (eGFR >= 60 ml/min per 1.73 m(2)) and a history of controlled hypertension and in healthy controls. Brachial artery flow-mediated dilation was also assessed after infusion of ascorbic acid to inhibit vascular oxidative stress compared with saline. Vascular endothelial cells were collected from a peripheral vein to measure expression of proteins, and circulating markers were also assessed by ELISA or liquid chromatography-tandem mass spectrometry.Results In total, 61 participants with autosomal dominant polycystic kidney disease (34 +/- 9 years old [mean +/- SD]) and 19 healthy controls (30 +/- 5 years old) were studied. Carotid-femoral pulse-wave velocity was higher in participants with autosomal dominant polycystic kidney disease compared with healthy controls (650 +/- 131 versus 562 +/- 81 cm/s; P=0.007). Brachial artery flow-mediated dilation was 8.2%+/- 5.8% in participants with autosomal dominant polycystic kidney disease and 10.8%+/- 4.7% in controls (P=0.08). Among participants with autosomal dominant polycystic kidney disease, flow-mediated dilation increased from 7.7%+/- 4.5% to 9.4%+/- 5.2% with ascorbic acid, a difference of 1.72 (95% confidence interval, 0.80 to 2.63), whereas in control participants, flow-mediated dilation decreased nonsignificantly from 10.8%+/- 4.7% to 10.6%+/- 5.4%, a difference of -0.20 (95% confidence interval, -1.24 to 0.84; P interaction =0.02). Endothelial cell protein expression of NF-B was greater in participants with autosomal dominant polycystic kidney disease (0.48 +/- 0.12 versus 0.41 +/- 0.10 [intensity versus human umbilical vein endothelial cell control]; P=0.03). However, circulating oxidative stress markers and bioactive lipid mediators did not significantly differ according to the autosomal dominant polycystic kidney disease diagnosis.Conclusions These results provide support for the hypothesis that vascular oxidative stress and inflammation develop with autosomal dominant polycystic kidney disease.