Microcirculation in Renovascular Hypertension

高血压是慢性肾脏疾病(CKD)的第二大病因，CKD是一种进行性疾病，几乎影响到 占总人口的14%。慢性肾脏病患者反过来与高血压(95%)有关，并有更高的 与非慢性肾脏病相比，住院率、医疗费用、心血管死亡率和预期寿命更短 病人。慢性肾血管病(Rvd)是引起肾血管性高血压的主要原因。 高达11%的美国成年人，CKD的风险增加25%。尽管有治疗RVD的方法可用， 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，突显了对这些患者进行新的治疗和策略的必要性。 具有较高的病死率和CKD风险。我们在HL095638上一个资助周期中的开创性工作 肾脏微循环的进行性损害和丧失是肾损伤的关键机制。 RVD中的高血压。我们还表明，使用重组人肾内单剂治疗 血管内皮生长因子(rh-VEGF)在很大程度上保护了肾脏微循环，改善了肾脏 在RVD和高血压的猪模型中发挥作用。这些影响是显著的，但仍不足以充分 尽管在RVD的早期阶段应用了血管内皮生长因子，但仍可逆转损伤或高血压。一个潜在的原因 对于肾脏损害的不完全解决是由于血管内皮生长因子的半衰期较短。最近，我们开发了一种 生物工程蛋白聚合物与重组人血管内皮生长因子融合，极大地稳定了血管内皮生长因子的降解和清除。 我们发现，这种以蛋白质为基础的聚合物，称为弹性蛋白样多肽(ELP)，自然积累在 肾脏中的高水平。我们令人信服的初步数据显示，单次肾内注射ELP- 血管内皮生长因子融合改善猪RVD模型的肾功能、微血管损伤和高血压 有效的免费的血管内皮生长因子疗法。此外，我们还开发了这种聚合物的工程版本，包含 肾靶向肽(KTP)，可进一步增加肾脏沉积和特异性(KTP-ELP)。因此， 拟议的HL095638更新研究将通过开发一种新的 具有很高临床转译潜力的治疗。我们最近开发并表征了KTP-ELP- 血管内皮细胞生长因子构建。这项建议将首先评估KTP-ELP改善肾脏沉积和 减少血管内皮生长因子的靶外结合。我们将确定特定的肾内定位和细胞类型结合 在体外和体内。我们将使用转基因小鼠模型和翻译猪RVD模型，并 收集推动高血压进展所需的药代动力学、生物分布、安全性和有效性数据 这项技术的临床试验。第二，我们将确定治疗效果和机制。 KTP-ELP-VEGF微创单剂量肾内给药对肾脏保护作用的改善 高血压、肾功能和微血管损伤。最后，我们将确定其疗效和作用机制。 KTP-ELP-血管内皮细胞生长因子(KTP-ELP-VEGF)治疗在全身、无创、单次给药(必要时重复给药)后。

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.