Department of Nephrology and Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands.
Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands.
Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1414-H1424. doi: 10.1152/ajpheart.00272.2018. Epub 2018 Jul 20.
Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.
心血管疾病占慢性肾脏病 (CKD) 患者死亡率的~50%。成纤维细胞生长因子 23 (FGF23) 与内皮功能障碍和心血管死亡率独立相关。我们假设 CKD 会损害微血管内皮功能，而这可能归因于 FGF23。小鼠接受部分肾切除术 (5/6Nx) 或假手术。为了评估 FGF23 的功能作用，非 CKD 小鼠接受 FGF23 注射，5/6Nx 手术后 CKD 小鼠接受 FGF23 阻断抗体。为了检查微血管功能，评估了小鼠体内心肌灌注和比目鱼肌阻力动脉的血管功能。5/6Nx 手术后，乙酰胆碱诱导的离体血管舒张反应减弱，而硝普钠或内皮素的反应正常。非 CKD 小鼠体内 FGF23 注射模拟了这种内皮缺陷，5/6Nx 小鼠中的 FGF23 抗体可预防内皮功能障碍。体外 FGF23 刺激微血管内皮细胞不会诱导 ERK 磷酸化。FGF23 增加了血浆不对称二甲基精氨酸浓度，并与内皮功能障碍强烈相关。增加的 FGF23 浓度不能模拟 5/6Nx 小鼠心肌中受损的内皮功能。总之，5/6Nx 小鼠外周内皮依赖性血管舒张受损是由 FGF23 介导的，并可通过阻断 FGF23 来预防。这些数据证实了 FGF23 是 CKD 中对抗心血管疾病的一个重要靶点。新内容和值得注意的内容：在本研究中，我们首次提供证据表明，成纤维细胞生长因子 23 (FGF23) 是早期慢性肾脏病 (CKD) 模型中外周内皮功能障碍的原因，并且 FGF23 阻断可预防 CKD 中的内皮功能障碍。这种对内皮细胞的病理作用是由生理水平的 FGF23 的长期暴露引起的。从机制上讲，增加的血浆不对称二甲基精氨酸浓度与 CKD 中的这种内皮功能障碍密切相关，并受 FGF23 影响。
