RANK-RANKL and Vascular Complications in Chronic Kidney Disease

描述(由申请人提供)：由于慢性肾脏疾病患者动脉粥样硬化和血管钙化的加速发展，心血管疾病的死亡率显著增加。心血管疾病的传统风险因素并不能完全解释这些加速的血管病变。我们已经证明，在缺乏骨保护素的小鼠中，动脉粥样硬化和血管钙化的发展速度加快。骨保护素是NFkB受体激活剂配体(RANKL)的诱饵受体。RANK-RANKL通过刺激破骨细胞分化，在骨稳态中发挥重要作用。我们还表明，喂食高脂饮食的尿毒症LDLR-/-小鼠加速了动脉粥样硬化病变的发展，并增加了主动脉RANK的表达。此外，用RANKL处理巨噬细胞和树突状细胞可以刺激促炎细胞因子的分泌。我们现在假设，慢性肾脏疾病中动脉粥样硬化和血管钙化的加速发展可能是由于RANKL的增加和巨噬细胞和树突状细胞中RANK信号的刺激。我们将用两个具体的目标来检验这一假设。在目标1中，我们将用弹枪蛋白质组学方法确定分泌蛋白质的特征，并使用微阵列技术在尿毒症小鼠的巨噬细胞和树突状细胞、慢性肾病患者的单核细胞以及RANKL治疗的巨噬细胞和树突状细胞中确定哪些促动脉粥样硬化和促钙化途径被激活，并可能解释加速的血管疾病。在第二个目标中，我们将把RANKL缺乏的小鼠的骨髓移植到尿毒症小鼠，并用抗RANKL治疗(OPG-FC)来治疗尿毒症小鼠，以确定阻断RANKL是否可以预防慢性肾脏疾病引起的动脉粥样硬化和血管钙化的加速。 公共健康相关性：公共健康相关性声明现在估计，超过15%的美国人口患有慢性肾脏疾病(CKD)。由于慢性肾脏病患者动脉粥样硬化和血管钙化的加速发展，心血管疾病的死亡率显著增加，而心血管疾病的传统危险因素并不能完全解释心血管死亡率的增加。因此，仍然需要定义和探索与慢性肾脏病相关的新途径，以帮助解释心血管风险的增加，并导致新的和独特的治疗方法。

DESCRIPTION (provided by applicant): There is a highly significant increase in mortality from cardiovascular disease due to accelerated development of atherosclerosis and vascular calcification in people with chronic kidney disease. Traditional risk factors for cardiovascular disease don't entirely explain these accelerated vascular pathologies. We have shown that there is accelerated development of atherosclerosis and vascular calcification in mice that are deficient in osteoprotegerin, a decoy receptor for the receptor activator of NFkB ligand (RANKL). RANK-RANKL plays an essential role in bone homeostasis by stimulating the differentiation of osteoclasts. We have also shown that uremic LDLR-/- mice fed a high fat diet have accelerated atherosclerotic lesion development and increased expression of RANK in the aorta. Furthermore, treatment of macrophages and dendritic cells with RANKL stimulates the secretion of pro-inflammatory cytokines. We now hypothesize that the accelerated development of atherosclerosis and vascular calcification in chronic kidney disease may be due to increased RANKL and the stimulation of RANK signaling in macrophages and dendritic cells. We will test this hypothesis with 2 specific aims. In aim 1, we will determine the signature of secreted proteins using shot-gun proteomics and the profile of expressed genes using microarrays in macrophages and dendritic cells from uremic mice and monocytes from people with chronic kidney disease as well as in macrophages and dendritic cells treated with RANKL in order to determine which pro-atherosclerotic and pro-calcification pathways are activated and may account for the accelerated vascular disease. In the second aim, we will transplant bone marrow from mice that are deficient in RANK into uremic mice and treat uremic mice with an anti-RANKL therapeutic (OPG-Fc) to determine whether blocking RANKL can protect against the accelerated atherosclerosis and vascular calcification that occurs with chronic kidney disease. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement It is now estimated that over 15% of the population of the United States have chronic kidney disease (CKD). There is a highly significant increase in mortality from cardiovascular disease due to accelerated development of atherosclerosis and vascular calcification in people with CKD and traditional risk factors for cardiovascular disease do not entirely explain this increase in cardiovascular mortality. Thus, there is a continuing need to define and explore new pathways associated with CKD that will help explain the increased cardiovascular risk and lead to new and unique therapeutic approaches.