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Published on: September 28, 2015
Role of Ciliary Neurotrophic Factor in Angiotensin II-Induced Hypertension
Sebastian A Potthoff1, Ivo Quack1, Yuri Mori2
1Department 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.).
Insights
Ciliary neurotrophic factor (CNTF) plays a key role in regulating blood pressure by modulating angiotensin II-induced responses. This cytokine impacts hypertension through a JAK2/STAT3-dependent pathway, highlighting its significance in cardiovascular regulation.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Ciliary neurotrophic factor (CNTF), a member of the IL-6 cytokine family, is primarily recognized for its neuroprotective effects.
- The influence of CNTF on vascular function and its role in hypertension remain largely unexplored.
- This study investigates the role of CNTF in angiotensin II (AngII)-induced hypertension.
Purpose of the Study:
- To elucidate the role of CNTF in the development and regulation of AngII-induced hypertension.
- To examine the impact of CNTF on vascular responses to AngII.
- To investigate the underlying molecular mechanisms, specifically the JAK2/STAT3 pathway, involved in CNTF's effects on blood pressure.
Main Methods:
- Utilized CNTF-knockout and wild-type mice to study AngII-induced hypertension.
- Measured blood pressure using tail-cuff and radiotelemetry methods.
- Assessed vascular function, renal pressor responses, and JAK2/STAT3 pathway activation in vivo, ex vivo (isolated perfused kidney), and in vitro (vascular smooth muscle cells).
Main Results:
- CNTF-knockout mice exhibited attenuated blood pressure increases and reduced hypertensive organ damage in response to AngII compared to wild-type mice.
- The renal pressor response to AngII was significantly decreased in CNTF-knockout mice, and this effect was partially restored by acute CNTF administration.
- CNTF was found to augment AngII-induced JAK2/STAT3 pathway activation in vascular smooth muscle cells, a mechanism crucial for its effect on blood pressure.
Conclusions:
- CNTF significantly impacts blood pressure regulation by modulating the AngII-induced pressor response.
- The observed effects of CNTF are mediated through a JAK2/STAT3-dependent mechanism.
- CNTF emerges as a critical regulatory cytokine in the context of hypertension.
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.
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