Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure

项目摘要 我们推进创新的心肾保护肽治疗心力衰竭（HF）。研究将 研究NPA 7，一种新的、多价的和一流的肽，由申请人工程化以共同靶向两种 生物途径。这两个目标是利钠肽/颗粒鸟苷酸环化酶-A 受体/cGMP和血管紧张素1 -7/MasR/cAMP系统。我们假设NPA 7介导心肾 通过这些互补途径具有保护性质，并具有超越pGC-A的协同作用， 单独激活MasR。重要的是，我们还假设NPA 7在一种状态下是非常有效的。 肾内肾素-血管紧张素-醛固酮系统（RAAS）过度活跃，如NPA 7可抑制醛固酮 产生/释放，拮抗AT 1，抑制肾素和抑制肾脏中的血管紧张素原（AGT）。 对实验性HF的初步研究表明，除了钠潴留和充血外，还有激活 肾脏中的有害分子途径的炎症，凋亡和纤维化，这可能会导致 肾功能和结构进行性恶化，结局较差。虽然多因素机制可能 血管紧张素II（ANG II）参与慢性HF中进行性肾结构和功能损害，是一种 基本调解人。在此，NPA 7通过pGC-A和MasR可以激活互补的RAAS抑制剂， 增强心肾保护的拮抗机制。我们还提出了尿的概念， AGT（uAGT）驱动肾脏生成ANG II，可作为一种新的病理生理学生物标志物 肾内RAAS激活，独立于循环RAAS。实际上，一个主要的长期目标是 开发uAGT作为肾内RAAS的新型尿液生物标志物，以帮助识别高风险 可能受益于NPA 7治疗的HF患者。目的1：确定的心肾保护性能 体外人肾小管细胞、心肌细胞以及肾和心肌成纤维细胞中的NPA 7。目标二： 确定慢性NPA 7治疗对心肾保护和肾内RAAS抑制的特性， 慢性HF的大型动物模型，其表现出心肌泵衰竭、肾灌注减少， 与ACEi相比，充血和肾内RAAS明显活化。目的3：测定小鼠中的uAGT水平 高风险慢性HF患者及其与肾功能受损的关系及其对未来的预测能力 HF住院和死亡。

PROJECT SUMMARY We advance innovative cardiorenal protective peptide therapeutics for heart failure (HF). Studies will investigate NPA7, a novel, multivalent and first-in-class peptide, engineered by the applicants to co-target two biological pathways. These two targets are the natriuretic peptide/particulate guanylyl cyclase-A receptor/cGMP and Angiotensin1-7/MasR/cAMP systems. We hypothesize that NPA7 mediates cardiorenal protective properties via these complementary pathways and has synergistic actions beyond pGC-A and MasR activation alone. Importantly, we also hypothesize that NPA7 is highly effective in a state of an overactive intrarenal renin-angiotensin-aldosterone system (RAAS) as NPA7 may suppress aldosterone production/release, antagonize AT1, suppress renin and inhibit angiotensinogen (AGT) in the kidney. Preliminary studies in experimental HF reveal that beyond sodium retention and congestion, there is activation of deleterious molecular pathways in the kidney for inflammation, apoptosis, and fibrosis, which may result in progressive worsening renal function and structure with poor outcomes. While multifactorial mechanisms may be involved in progressive renal structural and functional impairment in chronic HF, Angiotensin II (ANG II) is a fundamental mediator. Here NPA7, via pGC-A and MasR, may activate complementary RAAS inhibiting and antagonizing mechanisms with amplified cardiorenal protection. We also advance the concept that urinary AGT (uAGT), which drives the renal generation of ANG II, may serve as a novel pathophysiological biomarker for intrarenal RAAS activation, independent of circulating RAAS. Indeed, a major long-term goal is the development of uAGT as a novel urinary biomarker for intrarenal RAAS to aid in the identification of high-risk HF patients that may benefit from NPA7 therapy. Aim 1: Determine the cardiorenal protective properties of NPA7 in human renal tubular cells, cardiomyocytes and renal and myocardial fibroblasts in vitro. Aim 2: Determine cardiorenal protective and intrarenal RAAS suppressing properties of chronic NPA7 therapy in a large animal model of chronic HF that exhibits myocardial pump failure, reduced renal perfusion with congestion and markedly activated intrarenal RAAS compared to ACEi. Aim 3: Determine uAGT levels in high-risk chronic HF patients and its association with impaired renal function and its predictive power for future HF hospitalization and death.