PDF(Pubmed)
Abstract：
Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.
摘要：
高血压仍然是心血管和肾脏疾病的主要原因。使用≥3种药物或需要≥4种药物控制血压失败被归类为顽固性高血压（rHTN），需要新的疗法来降低由此导致的发病率和死亡率增加的风险。这里,我们报道了基因证据表明松弛素家族肽受体2（RXFP2）与男性rHTN相关，但不是女人。本研究显示RXFP2在男性高血压患者中肾上腺基因表达增高，RXFP2天然配体，INSL3增加人肾上腺细胞中的肾上腺类固醇生成和皮质类固醇分泌。为了解决RXFP2激活是rHTN中重要机制的假设，我们发现并鉴定了RXFP2的小分子和单克隆抗体（mAb）阻断剂。新的化学实体和单克隆抗体显示出有效的，选择性抑制RXFP2，减少醛固酮和皮质醇的合成和释放。RXFP2mAb具有合适的大鼠药代动力学特征来评估RXFP2在rHTN的开发和维持中的作用。总的来说,我们确定了RXFP2活性是rHTN中潜在的新机制,并发现了RXFP2拮抗剂,可用于将来在心血管和肾脏疾病中研究RXFP2.
