Hypoxia and inflammatory injury in human renovascular hypertension

描述(由申请人提供)：动脉粥样硬化性肾血管疾病(RVD)的肾损伤通常在恢复大血管通畅的情况下进展。这一过程与微血管稀疏、皮质缺氧、炎性细胞因子的刺激以及祖细胞和炎性细胞的招募有关。我们的总体假设是，人类RVD的肾脏损伤和恢复的严重程度不仅取决于血流的恢复，而且还取决于从促炎的、纤维化的表型转变为有利于恢复肾小管完整性的表型，这将反映M1(炎症)和M2(修复)的功能平衡。 巨噬细胞。该项目的具体目标是应用新技术来定义人类受试者的皮质和髓质血流和氧合。他们将与肾活检和肾静脉细胞因子模式的研究相结合，这些细胞因子模式可归因于M1或M2巨噬细胞。我们建议通过肾内移植具有免疫调节功能的自体脂肪间充质干细胞(MSCs)来改变炎症和血管生成途径。具体目标1将定义皮质和髓质血流、组织缺氧和炎症信号之间的关系，这些关系由RVD中跨肾细胞因子梯度定义。我们的假设是，皮质缺氧的水平(由血流量减少和脱氧血红蛋白升高定义)将与炎性归巢信号的诱导有关。具体目标2将致力于通过在晚期RVD中交付自体脂肪来源的MSCs来改善肾内微环境。需要检验的假设是，骨髓间充质干细胞将导致肾小球滤过、皮质和髓质血流明显增加，并 氧合，减少组织炎症，具有M2巨噬细胞的细胞因子特征。具体目标3将结合对晚期RVD患者通过肾动脉支架进行肾血管重建的MSC的管理。我们的假设是，与单独使用MSCs相比，MSCs联合肾动脉支架植入将增强组织修复，并将更好地恢复肾脏氧合和功能。这些研究将在人类中首次研究基于细胞的治疗在恢复肾脏血流后增强血管和功能修复的可能性。

DESCRIPTION (provided by applicant): Renal injury in atherosclerotic renovascular disease (RVD) often progresses despite restoring large vessel patency. This process is linked to rarefaction of microvessels, cortical hypoxia, stimulation of inflammatory cytokines and recruitment of progenitor and inflammatory cells. Our overall hypothesis is that the severity of renal injury and recovery in human RVD will depend upon not only restoration of blood flow but also a transition from a pro-inflammatory, fibrogenic phenotype to one favorable to restoring tubular integrity that will reflect the functional balance of M1 (inflammatory) and M2 (reparative) macrophages. The specific aims in this project apply novel technologies to define cortical and medullary blood flow and oxygenation in human subjects. They will be combined with studies of kidney biopsies and renal venous cytokine patterns that can be ascribed to M1 or M2 macrophages. We propose to modify the inflammatory and angiogenic pathways by delivering intra-renal autologous adipose-derived mesenchymal stem cells (MSCs) capable of immunomodulation. Specific Aim 1 will define the relationship between cortical and medullary blood flows, tissue hypoxia, and inflammatory signals, defined by trans-renal cytokine gradients in RVD. Our hypothesis is that the level of cortical hypoxia (defined both by blood flow reduction and elevated deoxyhemoglobin) will be related to induction of inflammatory homing signals. Specific Aim 2 will undertake to modify the intrarenal microenvironment by delivery of autologous adipose-derived MSCs in advanced RVD. The hypothesis to be tested is that MSCs will result in measurable increases in glomerular filtration, cortical and medullary blood flow and oxygenation, and reduced tissue inflammation with a cytokine signature characteristic of M2 macrophages. Specific Aim 3 will combine administration of MSC's to individuals with advanced RVD undergoing renal revascularization via renal artery stenting. Our hypothesis is that MSCs combined with renal artery stenting will augment tissue repair and will better restore kidney oxygenation and function than MSCs alone. These studies will provide the first investigation in humans of the potential for cell-based therapy to augment vascular and functional repair after restoring blood flow to the kidney.