Hypertension (Dallas, Tex. : 1979) · 2025
Role of Ciliary Neurotrophic Factor in Angiotensin II-Induced Hypertension.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.