Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients.
Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients.
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DOI：
10.1161/hypertensionaha.116.07849
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Lerman LO
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文献类型：
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作者：
Eirin A;Saad A;Tang H;Herrmann SM;Woollard JR;Lerman A;Textor SC;Lerman LO
线粒体损伤在几种肾脏疾病模型中导致肾功能不全，但其在人类高血压中的作用尚不清楚。从死亡细胞释放的线粒体基因组片段被认为是线粒体损伤的替代标记。我们假设高血压与尿线粒体DNA（mtDNA）拷贝数增加有关。我们前瞻性地检测了原发性高血压（EH，n=25）和肾血管性高血压（RVH，n=34）患者的全身和尿液mtDNA基因COX 3和ND 1拷贝数，并与健康志愿者（HV，n=22）进行比较。尿肾损伤分子（KIM）-1和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）作为肾损伤的指标。采用多排CT和BOLD-MRI评估肾血流量（RBF）和氧合。血压、尿NGAL和KIM-1在EH和RVH中相似地升高，并且估计的肾小球滤过率（eGFR）在RVH中低于HV和EH。与EH相比，RVH的RBF较低。高血压患者尿mtDNA拷贝数高于HV患者，与尿NGAL和KIM-1呈正相关，与eGFR呈负相关。在RVH中，尿mtDNA拷贝数与肾内缺氧直接相关。此外，在另一个验证队列中，RVH受试者的尿mtDNA拷贝数高于HV受试者（各n=10）。药物治疗后3个月血清肌酐水平和eGFR的变化与尿mtDNA的变化相关。因此，高血压患者尿mtDNA拷贝数升高与肾损伤和功能障碍的标志物相关，提示线粒体损伤与高血压患者的肾损伤有关。
Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes COX3 and ND1 by quantitative-PCR in essential (EH, n=25) and renovascular (RVH, n=34) hypertensive patients, and compared them with healthy volunteers (HV, n=22). Urinary kidney injury molecule (KIM)-1 and neutrophil gelatinase-associated lipocalin (NGAL) served as indices of renal injury. Renal blood flow (RBF) and oxygenation were assessed by multidetector-CT and BOLD-MRI. Blood pressure, urinary NGAL and KIM-1 were similarly elevated in EH and RVH, and estimated glomerular filtration rate (eGFR) lower in RVH versus HV and EH. RBF was lower in RVH compared to EH. Urinary mtDNA copy number was higher in hypertension compared to HV, directly correlated with urinary NGAL and KIM-1, and inversely with eGFR. In RVH, urinary mtDNA copy number correlated directly with intra-renal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared to HV subjects (n=10 each). The change in serum creatinine levels and eGFR 3-months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.