CARDIOVASCULAR RISK MECHANISMS IN CKD

描述(由申请人提供)：目前慢性肾脏疾病(CKD)正在流行。慢性肾脏病与肾脏疾病相关的心血管并发症的高死亡率有关。CKD患者心血管风险的本质尚不完全清楚，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，CKD患者的血磷水平与死亡风险相关，这种相关性是由于高磷血症与血管钙化之间的关系。最近的研究表明，在普通人群中，血磷与心血管危险有关，我们在翻译研究中发现了可能的作用机制，从而支持了PI作为心血管危险因子的作用。高磷血症，部分源于骨骼，刺激动脉粥样硬化斑块中细胞的成骨细胞转化，导致血管钙化。在CK中，高磷血症刺激了另一种成骨细胞特异性转录因子Osterix在动脉粥样硬化的主动脉中的表达，并增加了血管钙化。这些研究首次表明骨骼参与了慢性肾脏病的血管钙化。与血管钙化和心血管风险有关的CKD的一个重要并发症是动态骨病。在这一应用中，将寻求将肾脏疾病与动态骨骼疾病联系起来的新的病理生理学。最近的研究表明，CKD导致骨骼抑制因子的重新激活和释放。这一概念将在申请中得到贯彻。这一应用的远期目标是通过攻击病理生理机制来寻求治疗慢性肾脏疾病并发症的方法。应用的中心假设是肾脏疾病直接抑制导致CKD-MBD的骨骼功能，CKD-MBD是CKD心血管并发症的关键因素。应用的具体目的是：1)确定CKD产生骨骼抑制的机制：目的1的假设是肾脏疾病通过产生减少骨形成的循环因子而直接抑制骨骼功能。2)明确CKD-MBD导致CKD心血管危险的机制。目标二的假设是，CKD引起的骨骼重塑障碍导致与肾脏疾病相关的心血管并发症的刺激，而干预措施使CKD的骨骼重塑正常化，但没有直接的血管疗效作用，将减少与肾功能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.