Renal Osteodystrophy and Vascular Calcification

慢性肾脏病（CKD）及其并发症的病理生理学的最新进展， 重视高磷血症、血管钙化与CKD超额死亡率的关系。一 最近的发现表明，羟基磷灰石的骨骼沉积在以下水平中起重要作用： CKD中的血清磷。这一概念已经从进一步定义肾脏作为一种免疫系统的作用的研究中出现。 内分泌器官在不同组织的功能中相互作用。两个新的病理生理学原则， 从这些最近的研究中产生的，将在这个应用程序中进行测试。第一个新原则是， 肾损伤直接损害骨骼的韧性。二是肾性骨病和血管钙化 与高磷酸盐血症直接相关到目前为止，肾性骨营养不良被认为是由于 由于高磷酸盐血症和骨化三醇缺乏引起的低钙血症引起的继发性甲状旁腺功能亢进。 然而，最近，当钙、磷、甲状旁腺激素和骨化三醇的异常被避免时， 在CKD中，该疾病已显示与粘附性骨障碍有关。假设推导 从该观察结果可以看出，本申请中的研究将测试CKD损害骨骼的抗张性， 这发生在二价离子代谢异常之前，甚至参与了它们的产生。研究 第一个目的是进一步确立这一原则，并确定病理生理机制， 与CKD相关的骨骼合成代谢损失。一种正在开发的CKD治疗药物，骨 形态发生蛋白-7（BMP-7）是治疗肾性骨营养不良和血管钙化的有效药物。的 在本申请中寻求该试剂的作用机制，这将提供新的见解和新的 治疗和预防CKD及其并发症的治疗靶点。最近的研究发现， 在代谢综合征（胰岛素抵抗，肥胖， 高血压和血脂异常）。当在这些动物中产生消融性CKD时， 尽管存在继发性甲状旁腺功能亢进，但仍存在粘连性骨病。由于CKD也刺激了 在该模型中，这些研究提出了肾性骨营养不良和血管钙化的假设， 钙化是有直接联系的。第二个具体目标的研究检验了血清中 通过增加骨形成产生的磷导致血管钙化减少。的具体目标 应用：1、确定CKD引起的骨骼肌张力丧失的机制， 2、阐明BMP-7在代谢综合征血管钙化中的作用机制。 慢性肾脏疾病; 3，一方面证明高脂饮食与Wnt信号之间的相互作用， Wnt信号和BMP-7信号在CKD刺激的血管平滑肌中起重要作用。

Recent advances in the pathophysiology of chronic kidney disease (CKD) and its complications have called attention to the relationship between hyperphosphatemia, vascular calcification and excess mortality of CKD. A recent discovery demonstrates that skeletal apposition of hydroxyapatite plays an important role in the levels of serum phosphate in CKD. This concept has emerged from studies that further define the role of the kidney as an endocrine organ interacting in the function of different tissues. Two new pathophysiologic principles have emerged from these recent studies that will be tested in this application. The first new principle is that chronic renal injury directly impairs skeletal anabolism. The second is that renal osteodystrophy and vascular calcification are directly linked in part by hyperphosphatemia. Until now, renal osteodystrophy was thought to result from secondary hyperparathyroidism produced by hypocalcemia due to hyperphosphatemia and calcitriol deficiency. Recently, however, when abnormalities of calcium, phosphorus parathyroid hormone and calcitriol were avoided in CKD, the disease has been shown to be associated with an adynamic bone disorder. The hypothesis deriving from this observation that will be tested by studies in this application is that CKD impairs skeletal anabolism, and that this occurs before abnormalities in divalent ion metabolism and even participates in their production. Studies in the first aim are designed to further establish this principle and determine the pathophysiologic mechanism of anabolic loss in the skeleton associated with CKD. A therapeutic agent in development for CKD, bone morphogenic protein-7 (BMP-7), is an effectivetreatment for renal osteodystrophy and vascular calcification. The mechanisms of action of this agent are sought in this application which should provide new insights and new therapeutic targets for treatment and prevention of CKD and its complications. Recent studies have discovered a significant reduction of bone formation in an animal model of the metabolic syndrome (insulin resistance, obesity, hypertension and dyslipidemia). When ablative CKD was produced in these animals, the skeletal outcome was the adynamic bone disorder despite the presence of secondary hyperparathyroidism. Since CKD also stimulated vascular calcification in this model, these studies raise the hypothesis that renal osteodystrophy and vascular calcification are directly linked. Studies in the second specific aim test the hypothesis that reductions in the serum phosphorus produced by increasing bone formation result in reduced vascular calcification. The specific aims of the application are: 1, Determine the mechanisms of the loss of skeletal anabolism induced by CKD and the metabolic syndrome; 2, Demonstrate the mechanisms of BMP-7actions in the vascular calcification produced by chronic kidney disease; 3, Demonstrate the interactions between high fat diets and Wnt signaling on one hand, and Wnt signaling and BMP-7 on the other in the vascular smooth muscle stimulated by CKD.