Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh/British Heart Foundation Centre of Research Excellence, Edinburgh, UK.
Br J Clin Pharmacol. 2022 Dec;88(12):5295-5306. doi: 10.1111/bcp.15446. Epub 2022 Jul 19.
Chronic kidney disease (CKD) is common and cardiovascular disease (CVD) is its commonest complication. The apelin system is a potential therapeutic target for CVD but data relating to apelin in CKD are limited. We examined expression of the apelin system in human kidney, and investigated apelin and Elabela/Toddler (ELA), the endogenous ligands for the apelin receptor, in patients with CKD.
Using autoradiography, immunohistochemistry and enzyme-linked immunosorbent assay, we assessed expression of apelin, ELA and the apelin receptor in healthy human kidney, and measured plasma apelin and ELA in 155 subjects (128 patients with CKD, 27 matched controls) followed up for 5 years. Cardiovascular assessments included blood pressure, arterial stiffness (pulse wave velocity) and brachial artery flow-mediated dilation. Surrogate markers of endothelial function (plasma asymmetric dimethylarginine and endothelin-1) and inflammation (C-reactive protein and interleukin-6) were measured.
The apelin system was expressed in healthy human kidney, throughout the nephron. Plasma apelin concentrations were 60% higher in women than men (6.48 [3.62-9.89] vs. 3.95 [2.02-5.85] pg/mL; P < .0001), and increased as glomerular filtration rate declined (R = -0.41, P < .0001), and albuminuria rose (R = 0.52, P < .0001). Plasma apelin and ELA were associated with vascular dysfunction. Plasma apelin associated independently with a 50% decline in glomerular filtration rate at 5 years.
We show for the first time that the apelin system is expressed in healthy human kidney. Plasma apelin is elevated in CKD and may be a potential biomarker of risk of decline in kidney function. Clinical studies exploring the therapeutic potential of apelin agonism in CKD are warranted.
慢性肾脏病（CKD）很常见，心血管疾病（CVD）是其最常见的并发症。阿片肽系统是 CVD 的潜在治疗靶点，但有关 CKD 中阿片肽的资料有限。我们检查了人类肾脏中阿片肽系统的表达，并研究了 CKD 患者的阿片肽和 Elabela/Toddler（ELA），即阿片肽受体的内源性配体。
使用放射自显影、免疫组织化学和酶联免疫吸附试验，我们评估了健康人肾脏中阿片肽、ELA 和阿片肽受体的表达，并在 155 名受试者（128 名 CKD 患者和 27 名匹配的对照）中测量了 5 年的血浆阿片肽和 ELA。心血管评估包括血压、动脉僵硬度（脉搏波速度）和肱动脉血流介导的扩张。测量了内皮功能的替代标志物（血浆非对称二甲基精氨酸和内皮素-1）和炎症标志物（C 反应蛋白和白细胞介素-6）。
阿片肽系统在健康的人类肾脏中表达，遍布整个肾单位。女性的血浆阿片肽浓度比男性高 60%（6.48 [3.62-9.89] 对 3.95 [2.02-5.85] pg/mL；P < 0.0001），随着肾小球滤过率的下降而增加（R = -0.41，P < 0.0001），并随着白蛋白尿的增加而增加（R = 0.52，P < 0.0001）。血浆阿片肽和 ELA 与血管功能障碍有关。血浆阿片肽与 5 年内肾小球滤过率下降 50%独立相关。
我们首次表明阿片肽系统在健康的人类肾脏中表达。CKD 患者的血浆阿片肽升高，可能是肾功能下降风险的潜在生物标志物。需要进行临床研究，以探讨阿片肽激动剂在 CKD 中的治疗潜力。
