Therapeutics Division, 23andMe, 349 Oyster Point Blvd, South San Francisco, CA, 94080, USA.
Medicinal Science and Technology, GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
Sci Rep. 2024 Jun 8;14(1):13209. doi: 10.1038/s41598-024-62804-7.
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.
高血压仍然是心血管疾病和肾脏疾病的主要原因。如果使用≥3 种药物仍无法控制血压，或需要使用≥4 种药物才能控制血压，则将其归类为难治性高血压（rHTN），需要新的治疗方法来降低由此导致的发病率和死亡率增加的风险。在这里，我们报告遗传证据表明，松弛素家族肽受体 2（RXFP2）与男性的 rHTN 有关，但与女性无关。这项研究表明，高血压男性的肾上腺基因表达中 RXFP2 增加，而 RXFP2 的天然配体 INSL3 增加了人肾上腺细胞中的肾上腺甾体生成和皮质甾类分泌。为了解决 RXFP2 激活是 rHTN 重要机制的假设，我们发现并表征了 RXFP2 的小分子和单克隆抗体（mAb）抑制剂。这些新的化学实体和 mAbs 对 RXFP2 具有强大、选择性的抑制作用，并减少醛固酮和皮质醇的合成和释放。RXFP2 mAbs 具有适合大鼠药代动力学特征，可用于评估 RXFP2 在 rHTN 发展和维持中的作用。总的来说，我们确定了 RXFP2 活性作为 rHTN 的一个潜在新机制，并发现了 RXFP2 拮抗剂，用于进一步研究 RXFP2 在心血管和肾脏疾病中的作用。
