Matthew J Williams, Carmen M Halabi, Hiral M Patel, Zachary Joseph, Kyle McCommis, Carla Weinheimer, Attila Kovacs, Florence Lima, Brian Finck, Hartmut Malluche, Keith A Hruska
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Freshly excised cardiac tissue respirometry (Oroboros) showed that ADP-stimulated O<sub>2</sub> flux was diminished from 52 to 22 pmol/mg (<i>P</i> = 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. 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引用次数: 0
摘要
慢性肾脏病中的导管动脉疾病是导致心脏并发症的一个重要原因。在没有动脉疾病的情况下,还没有对慢性肾脏病的心脏功能进行过研究。在一个没有导管动脉疾病的 Alport 综合征模型中,出生 225 天(dol)的小鼠的 CKD 相当于人类的 4-5 期 CKD。PTH和FGF23水平升高了一个对数阶,循环硬蛋白升高,肾活化素A被强烈诱导。主动脉钙水平没有升高,VSMC 也没有发生转分化。CKD 小鼠没有高血压,也没有心肌肥大。新鲜切除的心脏组织呼吸测定(Oroboros)显示,ADP刺激的氧气通量从52 pmol/mg降至22 pmol/mg(p=0.044)。CKD 小鼠心脏组织的 RNAseq 结果显示,心脏线粒体氧化磷酸化基因的水平显著下降。为了研究激活素 A 信号转导的影响,一些 Alport 小鼠在出生后 75 天开始接受激活素 A 单克隆抗体或同种型匹配 IgG 的治疗,直至安乐死。使用活化素 A 抗体治疗不会影响心脏氧化磷酸化。然而,活化素 A 抗体在骨骼中具有活性,能破坏 CKD 刺激破骨细胞数量、侵蚀表面和刺激破骨细胞驱动重塑的作用。本文报告的数据显示,在没有导管动脉疾病的情况下,CKD 患者的心脏线粒体呼吸功能受损。这是首次报道 CKD 对心脏呼吸的直接影响。
In chronic kidney disease altered cardiac metabolism precedes cardiac hypertrophy.
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 O2 flux was diminished from 52 to 22 pmol/mg (P = 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.NEW & NOTEWORTHY 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.