CARDIOVASCULAR RISK MECHANISMS IN CKD

描述（由申请人提供）：目前慢性肾脏病（CKD）正在持续流行。CKD与肾脏疾病相关的心血管并发症相关的高死亡率相关。CKD患者心血管风险的性质尚不完全清楚，但CKD刺激的血管钙化和血管僵硬是重要的组成部分。观察性研究表明，血清磷与CKD的死亡风险相关，这种相关性是由于高磷血症和血管钙化之间的关系。最近的研究表明，在一般人群中，血清磷与心血管风险有关，我们在翻译研究中发现的假定作用机制支持了Pi作为心血管风险因素的作用。高磷酸盐血症，部分来源于骨骼，刺激动脉粥样硬化斑块中细胞的成骨转变，导致血管钙化。在CK中，高磷酸盐血症刺激了第二种成骨细胞特异性转录因子osterix在动脉粥样硬化主动脉中的表达，并增加了血管钙化。这些研究首次表明骨骼参与了CKD的血管钙化。与血管钙化和心血管风险相关的CKD的一个重要并发症是粘附性骨病。在本申请中，将寻求将肾脏疾病与粘连性骨病联系起来的新病理生理学。最近的研究表明，CKD引起骨骼抑制因子的再激活和释放到循环中。这一概念将在申请中得到贯彻。本申请的长期目标是通过攻击病理生理学机制来治疗慢性肾脏疾病并发症。本申请的中心假设是肾脏疾病直接抑制引起CKD-MBD的骨骼功能，并且CKD-MBD是CKD的心血管并发症的关键因素。本申请的具体目的是：1）确定CKD产生的骨骼抑制机制：目的一的假设是肾脏疾病通过产生减少骨形成的循环因子直接抑制骨骼功能。2)确定CKD-MBD导致CKD心血管风险的机制。目的二的假设是，由CKD产生的骨骼重塑障碍引起与肾脏疾病相关的心血管并发症的刺激，并且使CKD中的骨骼重塑正常化但没有直接的血管功效作用的干预将减少与肾衰竭相关的心血管疾病。

DESCRIPTION (provided by applicant): There is a current ongoing pandemic of chronic kidney disease (CKD). CKD is associated with high mortality rates related to cardiovascular complications associated with kidney disease. The nature of the cardiovascular risk in CKD is incompletely understood, but CKD stimulated vascular calcification and vascular stiffness are important components. Observational studies suggest that the serum phosphate is associated with mortality risk in CKD, and that the association is due to the relationship between hyperphosphatemia and vascular calcification. Recent studies have suggested that the serum phosphorus is associated with cardiovascular risk in the general population, and the role of Pi as a cardiovascular risk factor has been supported by our discovery of putative mechanisms of action in traslational studies. Hyperphosphatemia, in part deriving from the skeleton, stimulates osteoblastic transition of cell in atherosclerotic plaques leading to vascular calcification. In CK hyperphosphatemia stimulated the expression of a second osteoblast specific transcription factor, osterix in the atherosclerotic aorta, and increased vascular calcification. These studies were the first to suggest that the skeleton participated in vascular calcification in CKD. An important complication of CKD linked to vascular calcification and cardiovascular risk is the adynamic bone disorder. New pathophysiology linking kidney disease to the adynamic bone disorder will be pursued in this application. Recent studies demonstrate that CKD causes reactivation and release to the circulation of skeletal inhibitory factors. This concept will be pursued in the application. The long-range objective of this application is to pursue treatment of chronic kidney disease complications through attacking the mechanisms of pathophysiology. The central hypothesis of the application is that kidney disease directly inhibits skeletal functio causing the CKD-MBD, and that the CKD-MBD is a critical factor in the cardiovascular complications of CKD. The specific aims of the application are to: 1) Determine the mechanisms of skeletal inhibition produced by CKD: The hypothesis of aim one is that kidney disease directly inhibits skeletal function by producing circulating factors that decrease bone formation. 2) Determine the mechanisms by which the CKD-MBD causes cardiovascular risk in CKD. The hypotheses of aim two are that the skeletal remodeling disorder produced by CKD causes stimulation of cardiovascular complications associated with kidney diseases, and that interventions, which normalize skeletal remodeling in CKD but have no direct vascular efficacy actions, will diminish the cardiovascular disease associated with kidney failure.