Emschermann Frederic, Zuern Christine S, Patzelt Johannes, Rizas Konstantinos D, Jäger Günter, Eick Christian, Meuth Sven G, Gawaz Meinrad, Bauer Axel, Langer Harald F
University Hospital, Department of Cardiology and Cardiovascular Medicine, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
Institut für Genetik und angewandte Genomik, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
Int J Cardiol Heart Vasc. 2016 Apr 29;11:80-86. doi: 10.1016/j.ijcha.2016.04.001. eCollection 2016 Jun.
Factors causing resistance to renal denervation (RDN) for treatment of arterial hypertension are not known. In the current study, we sought to determine mechanisms involved in responsiveness to renal denervation therapy in patients with difficult-to-control and resistant hypertension.
We evaluated the differential CpG methylation of genes in blood samples isolated from patients of a recently described cohort of responders or non-responders to renal denervation using microarray technique and measured protein levels of identified downstream effectors in blood samples of these patients by ELISA. Our analysis revealed up to 6103 methylation sites differing significantly between non-responders and responders to renal denervation therapy. Software based analysis showed several of these loci to be relevant for arterial hypertension and sympathetic nervous activity. Particularly, genes involved in glutamate synthesis, degradation and glutamate signaling pathways were differently methylated between both groups. For instance, genes for glutamate dehydrogenase 1 and 2 central to glutamate metabolism, genes for ionotropic (AMPA, NMDA) and metabotropic glutamate receptors as well as glutamate transporters revealed significant differences in methylation correlating with responsiveness to RDN. To underline their potential relevance for responsiveness to RDN, we measured plasma protein levels of norepinephrine, a downstream effector of the glutamate receptor pathway, which were significantly lower in non-responders to RDN.
The present study describes novel molecular targets potentially contributing to reduction of blood pressure after RDN in some patients. Identifying patients with a high responsiveness to RDN could contribute to an individualized therapy in drug resistant hypertension.
导致肾去神经支配（RDN）治疗动脉高血压产生抵抗的因素尚不清楚。在本研究中，我们试图确定难治性和顽固性高血压患者对肾去神经支配治疗反应性的相关机制。
我们使用微阵列技术评估了从最近描述的肾去神经支配反应者或无反应者队列患者的血液样本中基因的差异CpG甲基化，并通过酶联免疫吸附测定法测量了这些患者血液样本中已鉴定的下游效应物的蛋白质水平。我们的分析显示，肾去神经支配治疗的无反应者和反应者之间有多达6103个甲基化位点存在显著差异。基于软件的分析表明，其中几个位点与动脉高血压和交感神经活动相关。特别是，参与谷氨酸合成、降解和谷氨酸信号通路的基因在两组之间甲基化情况不同。例如，谷氨酸代谢核心的谷氨酸脱氢酶1和2的基因、离子型（AMPA、NMDA）和代谢型谷氨酸受体的基因以及谷氨酸转运体的基因显示甲基化存在显著差异，这与对RDN的反应性相关。为强调它们对RDN反应性的潜在相关性，我们测量了谷氨酸受体途径的下游效应物去甲肾上腺素的血浆蛋白水平，在RDN无反应者中该水平显著较低。
本研究描述了一些可能有助于部分患者RDN后血压降低的新分子靶点。识别对RDN反应性高的患者有助于耐药性高血压的个体化治疗。
