Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States.
Geriatrics and Nutritional Science Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States.
Am J Physiol Renal Physiol. 2024 May 1;326(5):F751-F767. doi: 10.1152/ajprenal.00416.2023. Epub 2024 Feb 22.
Conduit arterial disease in chronic kidney disease (CKD) is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to humans with CKD stage 4-5. Parathyroid hormone (PTH) and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased, and vascular smooth muscle cell (VSMC) transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed that ADP-stimulated O flux was diminished from 52 to 22 pmol/mg ( = 0.022). RNA-Seq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. To examine the effect of activin A signaling, some Alport mice were treated with a monoclonal Ab to activin A or an isotype-matched IgG beginning at 75 days of life until euthanasia. Treatment with the activin A antibody (Ab) did not affect cardiac oxidative phosphorylation. However, the activin A antibody was active in the skeleton, disrupting the effect of CKD to stimulate osteoclast number, eroded surfaces, and the stimulation of osteoclast-driven remodeling. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration. Heart disease is an important morbidity of chronic kidney disease (CKD). Hypertension, vascular stiffness, and vascular calcification all contribute to cardiac pathophysiology. However, cardiac function in CKD devoid of vascular disease has not been studied. Here, in an animal model of human CKD without conduit arterial disease, we analyze cardiac respiration and discover that CKD directly impairs cardiac mitochondrial function by decreasing oxidative phosphorylation. Protection of cardiac oxidative phosphorylation may be a therapeutic target in CKD.
慢性肾脏病（CKD）患者的动脉疾病是心脏并发症的一个重要原因。在没有动脉疾病的情况下，尚未研究 CKD 患者的心脏功能。在一种不发生动脉疾病的 Alport 综合征模型中，225 日龄（dol）的小鼠出现与 CKD 4-5 期患者相当的 CKD。甲状旁腺激素（PTH）和 FGF23 水平升高一个对数级，循环中硬骨素升高，肾脏中的激活素 A 强烈诱导。主动脉 Ca 水平没有升高，血管平滑肌细胞（VSMC）转化不存在。CKD 小鼠没有高血压，也没有心脏肥大。新鲜取出的心脏组织呼吸测定法（Oroboros）显示，ADP 刺激的 O 通量从 52 减少到 22 pmol/mg（=0.022）。CKD 小鼠心脏组织的 RNA-Seq 显示，心脏线粒体氧化磷酸化基因的水平显著降低。为了研究激活素 A 信号的作用，一些 Alport 小鼠从 75 日龄开始用抗激活素 A 单克隆抗体或同型 IgG 治疗，直至安乐死。用激活素 A 抗体（Ab）治疗不会影响心脏氧化磷酸化。然而，激活素 A 抗体在骨骼中是有效的，破坏了 CKD 刺激破骨细胞数量、侵蚀表面和刺激破骨细胞驱动的重塑的作用。本报告中报道的数据表明，在没有动脉疾病的情况下，CKD 会损害心脏线粒体呼吸。这是 CKD 对心脏呼吸的直接影响的首次报道。心脏病是慢性肾脏病（CKD）的一个重要发病率。高血压、血管僵硬和血管钙化都对心脏病理生理学有影响。然而，在没有血管疾病的 CKD 患者中，尚未研究心脏功能。在这里，在一种没有动脉疾病的人类 CKD 动物模型中，我们分析了心脏呼吸，并发现 CKD 通过降低氧化磷酸化直接损害心脏线粒体功能。保护心脏氧化磷酸化可能是 CKD 的一个治疗靶点。
