Renal Osteodystrophy and Vascular Calcification

慢性肾脏病(CKD)及其并发症的病理生理学研究进展 注意高磷血症、血管钙化与CKD病死率的关系。一个 最近的发现表明，羟基磷灰石的骨骼堆积在以下水平中起着重要作用 慢性肾脏病患者的血磷水平。这一概念是从进一步定义肾脏作为一种 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理 从这些最近的研究中出现，这些研究将在这一应用中进行测试。第一个新原则是慢性 肾损伤直接损害骨骼合成代谢。二是肾性骨营养不良和血管钙化 在一定程度上与高磷血症有关。到目前为止，肾性骨病被认为是由 继发性甲状旁腺功能亢进症，由高磷血症和骨化三醇缺乏引起的低钙血症引起。 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 在慢性肾脏病中，这种疾病已被证明与一种动态的骨病有关。假设的派生 根据这一观察结果，这项应用中的研究将检验CKD损害骨骼合成代谢，以及 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，并确定其病理生理机制。 与慢性肾脏病相关的骨骼中的合成代谢缺失。一种正在开发中的CKD治疗剂--骨 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。这个 在这一应用中寻求该试剂的作用机制，应提供新的见解和新的 治疗和预防慢性肾脏病及其并发症的治疗目标。最近的研究发现， 代谢综合征动物模型(胰岛素抵抗、肥胖、 高血压和血脂异常)。当这些动物产生消融性CKD时，骨骼结局是 尽管存在继发性甲状旁腺功能亢进，但仍存在动态骨病。因为CKD还刺激了 在这个模型中，这些研究提出了肾性骨营养不良和血管钙化的假设 钙化是直接相关的。第二个特定目标的研究检验了这样的假设：血清中 增加骨形成所产生的磷会减少血管钙化。的具体目标 其应用是：1、确定慢性肾脏病所致骨骼合成代谢丧失的机制，并探讨其作用机制。 代谢综合征；2，阐明BMP-7在血管钙化中的作用机制 慢性肾脏疾病；3，一方面证明了高脂饮食和Wnt信号之间的相互作用， 在CKD刺激的血管平滑肌中，Wnt信号和BMP-7的表达也不同。

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.