Microcirculation in Renovascular Hypertension

肾血管性高血压的微循环

基本信息

批准号：
10670589
负责人：
Alejandro Roberto Chade
金额：
$ 50.72万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670589
关键词：
Microcirculation Renovascular Hypertension

项目摘要

Hypertension is the 2nd major etiology of chronic kidney disease (CKD), a progressive disorder affecting almost 14% of the general population. Patients with CKD in turn associates to hypertension (< 95%) and have higher rates of hospitalization, healthcare costs, cardiovascular mortality, and shorter life expectancy than non-CKD patients. Chronic renovascular disease (RVD) is the main cause of renovascular hypertension that develops in up to 11% of the US adults and increases risk of CKD by 25%. Despite the availability of treatments for RVD, renal function and hypertension do not improve or even deteriorates in over half of the patients, showing that treatments are still ineffective and highlighting the need of new treatments and strategies for these patients with higher mortality and risk of CKD. Our seminal work during the previous funding cycle of HL095638 showed that a progressive damage and loss of the renal microcirculation is a pivotal mechanism for renal injury and hypertension in RVD. We also showed that intra-renal single-dose therapy using recombinant human vascular endothelial growth factor (rh-VEGF) largely preserved the renal microcirculation and improved renal function in a swine model of RVD and hypertension. These effects were significant but still insufficient to fully reverse injury or hypertension despite VEGF being administered at an early stage of RVD. A potential reason for the incomplete resolution of renal damage is the short half-life of VEGF. Recently, we have developed a bioengineered protein polymer fused to rh-VEGF that greatly stabilizes VEGF from degradation and clearance. We showed that this protein-based polymer, called Elastin-like Polypeptide (ELP), naturally accumulates at high levels in the kidney. Our compelling preliminary data show that single intra-renal administration of an ELP- VEGF fusion improved renal function, microvascular injury, and hypertension in the swine RVD model more efficiently that free VEGF therapy. In addition, we developed engineered versions of the polymer, containing kidney targeting peptides (KTP) that further increase kidney deposition and specificity (KTP-ELP). Thus, the proposed studies in the renewal of HL095638 will extend the previous contributions by developing a new treatment with high potential for clinical translation. We recently developed and characterized a KTP-ELP- VEGF construct. This proposal will first assess the effectiveness of KTP-ELP to improve renal deposition and reduce off-target binding of VEGF. We will determine the specific intra-renal localization and cell-type binding in vitro and in vivo. We will use genetically modified mice models and a translational swine model of RVD and hypertension to collect pharmacokinetic, biodistribution, safety, and efficacy data needed to propel the advance of this technology towards clinical testing. Second, we will determine the therapeutic efficacy and mechanisms of renoprotection of minimally invasive single-dose intra-renal administration of KTP-ELP-VEGF to improve hypertension, renal function and microvascular injury. Finally, we will determine the efficacy and mechanisms of KTP-ELP-VEGF therapy after systemic, non-invasive, single-dose (repeated if needed) administration.

高血压是慢性肾脏病 (CKD) 的第二个主要病因，这是一种进行性疾病，影响几乎占总人口的14%。慢性肾病 (CKD) 患者又与高血压相关 (< 95%)，并且具有较高的与非 CKD 相比，住院率、医疗费用、心血管死亡率和预期寿命更短患者。慢性肾血管病（RVD）是肾血管性高血压的主要原因。高达 11% 的美国成年人患有慢性肾病 (CKD) 风险增加 25%。尽管有 RVD 的治疗方法，超过一半的患者肾功能和高血压没有改善甚至恶化，这表明治疗仍然无效，凸显了这些患者需要新的治疗和策略死亡率和 CKD 风险较高。我们在 HL095638 上一个资助周期中的开创性工作研究表明肾微循环的进行性损伤和丧失是肾损伤的关键机制和 RVD 中的高血压。我们还表明，使用重组人进行肾内单剂量治疗血管内皮生长因子（rh-VEGF）在很大程度上保留了肾脏微循环并改善了肾功能在 RVD 和高血压猪模型中发挥作用。这些影响是显着的，但仍不足以充分尽管在 RVD 的早期阶段施用 VEGF，但仍能逆转损伤或高血压。一个潜在的原因肾损伤不能完全解决的原因是 VEGF 的半衰期短。最近，我们开发了一个与 rh-VEGF 融合的生物工程蛋白质聚合物，可极大地稳定 VEGF 的降解和清除。我们证明，这种基于蛋白质的聚合物，称为类弹性蛋白多肽（ELP），可以自然地积累在肾脏中含量高。我们令人信服的初步数据表明，单次肾内注射 ELP- VEGF 融合改善猪 RVD 模型中的肾功能、微血管损伤和高血压有效的免费 VEGF 疗法。此外，我们还开发了聚合物的工程版本，其中包含肾脏靶向肽（KTP）进一步增加肾脏沉积和特异性（KTP-ELP）。因此，更新 HL095638 时提出的研究将通过开发新的方法来扩展之前的贡献具有高度临床转化潜力的治疗。我们最近开发并表征了 KTP-ELP- VEGF 构建体。该提案将首先评估 KTP-ELP 改善肾沉积和减少 VEGF 的脱靶结合。我们将确定特定的肾内定位和细胞类型结合体外和体内。我们将使用转基因小鼠模型和 RVD 的转化猪模型高血压收集推动进展所需的药代动力学、生物分布、安全性和功效数据将该技术用于临床测试。其次，我们将确定治疗效果和机制微创单剂量肾内注射 KTP-ELP-VEGF 改善肾脏保护作用高血压、肾功能和微血管损伤。最后，我们将确定功效和机制全身、非侵入性、单剂量（如果需要重复）给药后的 KTP-ELP-VEGF 治疗。