Role of CC chemokine signaling in hyperglycemic renal artery stenosis

描述(由申请人提供)：动脉粥样硬化性肾动脉狭窄(RAS)引起的肾血管性高血压(RVH)患者的最佳治疗是一个相当有争议的问题。我们的长期目标是在RVH的2肾1夹模型中确定导致狭窄肾的缺血性损伤和对侧肾的高血压损伤的信号通路。我们最近的研究强调了单核细胞趋化蛋白-1(CCL2)和CC趋化因子家族的其他成员在小鼠RVH慢性肾损害发生中的关键作用。CC趋化因子的表达在代谢综合征和糖尿病(Mets-D)患者肾脏疾病的进展中起关键作用，但对其在肾血管疾病(RVD)中的作用知之甚少。大多数研究集中在循环炎症细胞和组织巨噬细胞产生趋化因子，尽管实质细胞可以产生CC趋化因子，从而促进损伤。在我们正在进行的研究中，下一个合乎逻辑的步骤是阐明CC趋化因子信号的关键作用 通过肾实质细胞和渗透的巨噬细胞和其他炎症细胞在RVD的进展中，以及Mets-D的存在如何调节这一过程。我们正在进行的研究的中心假设是，CC趋化因子信号引导巨噬细胞内流和极化的早期事件，导致慢性损伤，实质细胞产生的趋化因子可能参与/放大这一过程。此外，我们的初步研究表明，巨噬细胞在对侧肾脏慢性损害的发生中起着重要作用，这一过程依赖于Mets-D的存在。我们的目的是1)检验CC趋化因子在介导Mets-D和RVH小鼠双侧慢性肾损伤发生发展中起关键作用的假设；2)测试Mets-D和RVH小鼠CKD的进展需要CC趋化因子信号通过骨髓来源的巨噬细胞和实质细胞相互作用的假说；以及3)测试M1极化对于Mets-D和RVH小鼠肾脏疾病的启动和发展是必需的假说。拟议的研究将为理解巨噬细胞极化和CC趋化因子产生在Mets-D新的RVH小鼠模型慢性肾脏损害发展中的机制作用提供必要的基础。

DESCRIPTION (provided by applicant): Optimal management of patients with renovascular hypertension (RVH) due to atherosclerotic renal artery stenosis (RAS) is a matter of considerable controversy. Our long-term goal is to identify signaling pathways responsible for the development of ischemic injury in the stenotic kidney and hypertensive injury in the contralateral kidney in the 2-kidney, 1-clip model of RVH. Our recent studies have underscored a critical role for MCP-1 (CCL2) and other members of the CC chemokine family in the development of chronic renal damage in murine RVH. CC chemokine expression plays a critical role in the progression of renal disease in patients with metabolic syndrome and diabetes (MetS-D), but less is known about their role in renovascular disease (RVD). Most studies have focused on chemokine generation by circulating inflammatory cells and tissue macrophages, although parenchymal cells can produce CC chemokines and thereby contribute to injury. The next logical step in our ongoing studies is to elucidate a critical role for CC chemokine signaling by renal parenchymal cells and infiltrating macrophages and other inflammatory cells in the progression of RVD and how this process is modulated by the presence of MetS-D. The central hypothesis underlying our ongoing studies is that CC chemokine signaling directs early events in macrophage influx and polarization, leading to chronic injury, and that chemokine generation by parenchymal cells may contribute to/amplify this process. Furthermore, macrophages play an important role in the development of chronic renal damage in the contralateral kidney, a process that depends on the presence of MetS-D, as suggested by our preliminary studies. Our aims are to 1) test the hypothesis that CC chemokines play a critical role in mediating the development and progression of bilateral chronic renal injury in mice with MetS-D and RVH; 2) test the hypothesis that progression of CKD in mice with MetS-D and RVH requires interaction of CC chemokine signaling through bone marrow derived macrophages and parenchymal cells; and 3) test the hypothesis that M1 polarization is necessary for initiation and progression of renal disease in MetS-D mice with RVH. The proposed studies will provide an essential foundation towards understanding a mechanistic role for macrophage polarization and CC chemokine generation in the development of chronic renal lesions in a novel mouse model of RVH with MetS-D.