Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

项目摘要/摘要 外周动脉疾病(PAD)是由下肢动脉粥样硬化引起的 一系列改变生活的症状，包括跛行、缺血性休息疼痛和坏疽需要 截肢。使PAD的病因学复杂化的是，患者通常存在共同的条件或风险 加速疾病演变和显著恶化病理的因素导致死亡率增加 风险。其中，慢性肾脏病(CKD)加速动脉粥样硬化的发展，减少 功能能力，并增加截肢或死亡的风险，但其潜在的生物机制(S) 与其他合并症(如吸烟和糖尿病)相比，人们对此知之甚少，研究也极少。 我们发现了一条可能将CKD和PAD病理生物学联系起来的新的分子途径。我们发现有那么多 尿毒症代谢物在慢性肾脏病中积聚，导致芳香烃受体(AHR)的慢性激活 这会导致线粒体电子传递系统的中断，从而加剧肌肉缺血 损伤和损害血管生成。初步实验表明，AHR的基因敲除是 对尿毒症毒性的保护，而结构性活性AHR的表达导致线粒体 功能障碍。因此，我们建议检验这一新的假设，即AHR通路的慢性激活 导致缺血性肌肉损伤和血管生成受损，从而将CKD和PAD病理生物学联系起来。这 假说将通过肌肉和血管特异性诱导的AHR以及腺相关基因的敲除来验证。 CKD/PAD临床前期模型中α成分活性AHR相关病毒介导的表达。 最后，我们最近的人类数据表明，慢性肾脏病患者的AHR信号升高。我们建议 扩展这些发现以建立肌肉健康/功能、线粒体能量学和 人类PAD患者的AHR信号转导。这些研究的成功将为我们提供对 CKD对PAD病理生物学的影响，并将为旨在治疗的开发提供新的靶点 治疗目前几乎没有可用选择的患者群体。

PROJECT SUMMARY/ABSTRACT Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s) are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes). We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR) which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno- associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD. Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to treat a patient population that currently has few available options.