Potthoff Sebastian A, Quack Ivo, Mori Yuri, Yang Guang, Arifaj Denada, Amin Ehsan, Meister Jaroslawna, Meuth Sven G, Kantauskaite Marta, Argov Doron, Alesutan Ioana, Voelkl Jakob, Park Joon-Keun, Rump Lars C, Rio Marc, Loirand Gervaise, Linker Ralf A, Stegbauer Johannes
Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.).
Department of Nuclear Medicine, Medical Faculty of Heinrich Heine University, University Hospital Düsseldorf, Germany (Y.M.).
Hypertension. 2025 Apr;82(4):652-664. doi: 10.1161/HYPERTENSIONAHA.124.22845. Epub 2025 Jan 24.
Ciliary neurotrophic factor (CNTF), mainly known for its neuroprotective properties, belongs to the IL-6 (interleukin-6) cytokine family. In contrast to IL-6, the effects of CNTF on the vasculature have not been explored. Here, we examined the role of CNTF in AngII (angiotensin II)-induced hypertension.
Hypertension was chronically induced with AngII (1000 ng/kg per minute, osmotic mini-pumps, 14 days) in CNTF-knockout and wild-type mice (with or without nephrectomy and 1% NaCl drinking water). Blood pressure was measured by tail-cuff and radiotelemetry. Effects of CNTF on vascular function and the JAK2/STAT3 pathway were measured in vivo, in the isolated perfused kidney, and in mouse and human vascular smooth muscle cells.
At baseline, systolic blood pressure was similar between both groups. During AngII infusion, blood pressure increase was significantly attenuated and hypertensive heart and kidney damage was significantly attenuated in CNTF-knockout compared with wild-type mice. Accordingly, renal pressor response to AngII but not KCl or phenylephrine was significantly decreased in CNTF-knockout compared with wild-type mice. Acute CNTF (5 µmol/L) administration nearly restored the AngII-dependent renal pressor response. Chronic CNTF treatment in CNTF-knockout mice increased blood pressure response to AngII to levels observed in wild-type mice. CNTF augments AngII-induced activation of the JAK2/STAT3 pathway in vitro in vascular smooth muscle cells. The significance of this interaction was shown, as the increase in renal pressor response by CNTF was abolished by JAK2/STAT3 inhibitors.
Our results demonstrate a major impact of CNTF on blood pressure regulation by modulating AngII-induced pressor response via a JAK2/STAT3-dependent mechanism and indicate that CNTF is an important regulatory cytokine in hypertension.
睫状神经营养因子（CNTF）主要因其神经保护特性而闻名，属于白细胞介素-6（IL-6）细胞因子家族。与IL-6不同，CNTF对脉管系统的作用尚未得到研究。在此，我们研究了CNTF在血管紧张素II（AngII）诱导的高血压中的作用。
在CNTF基因敲除小鼠和野生型小鼠（有或没有肾切除及饮用1%氯化钠溶液）中，通过AngII（每分钟1000 ng/kg，渗透微型泵，持续14天）长期诱导高血压。通过尾套法和无线电遥测法测量血压。在体内、离体灌注肾以及小鼠和人血管平滑肌细胞中，检测CNTF对血管功能和JAK2/STAT3信号通路的影响。
在基线时，两组的收缩压相似。在输注AngII期间，与野生型小鼠相比，CNTF基因敲除小鼠的血压升高明显减弱，高血压性心脏和肾脏损伤也明显减轻。相应地，与野生型小鼠相比，CNTF基因敲除小鼠对AngII而非氯化钾或去氧肾上腺素的肾加压反应显著降低。急性给予CNTF（5 μmol/L）几乎恢复了AngII依赖性肾加压反应。在CNTF基因敲除小鼠中进行慢性CNTF治疗，可使对AngII的血压反应增加至野生型小鼠中观察到的水平。CNTF在体外可增强血管平滑肌细胞中AngII诱导的JAK2/STAT3信号通路的激活。JAK2/STAT3抑制剂消除了CNTF引起的肾加压反应增加，从而证明了这种相互作用的重要性。
我们的结果表明，CNTF通过JAK2/STAT3依赖性机制调节AngII诱导的加压反应，从而对血压调节产生重大影响，并表明CNTF是高血压中的一种重要调节细胞因子。
