Afferent renal nerves, renal inflammation, and hypertension
Afferent renal nerves, renal inflammation, and hypertension
批准号:
10308480
负责人:
John W Osborn
金额:
$51.12万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-12-15 至 2023-10-31
关键词:
AblationAnatomyAntihypertensive AgentsAttenuatedBiological MarkersBiological Response ModifiersBrainCathetersCellsChronic Kidney FailureClinicalClinical TrialsConduct Clinical TrialsDOCADenervationDevelopmentDiagnostic testsDiastolic blood pressureDiseaseDrug TargetingDrug resistanceEfferent NeuronsFailureFollow-Up StudiesHumanHypertensionImmuneInflammationInflammatoryInflammatory ResponseKidneyLaboratoriesLinkMaintenanceMediatingMethodsMolecular TargetMorbidity - disease rateMusNerveNeuraxisPathogenesisPatientsPelvisPeripheralPharmacologyPhasePhysiologicalPreparationRat-1RattusRenal functionResearchRoleSliceSodium ChlorideSympathetic Nervous SystemSystolic PressureT-LymphocyteTestingTrainingTranslationsUnited StatesUrineafferent nervebasecytokinediagnostic biomarkerhemodynamicshypertension treatmenthypertensiveinsightmortalityneurophysiologyneuroregulationnew therapeutic targetnormotensivenovelpressurepublic health relevanceresponsesalt sensitive hypertensiontheoriestranslational barriertreatment responsetrial designurinary
中文摘要
摘要
高血压(HTN)与交感神经系统活动(SNA)增加和
肾传出神经的活动被认为是重要的。然而,肾脏也受到肾脏的支配。
传入神经,投射到中枢神经系统回路,将SNA调制到各种外周
目标。因此,肾传入神经活动(ARNA)的增加也被认为是导致
SNA与HTN的发病机制。肾去神经(RDNx)治疗人类HTN现在是
有可能。然而,RDNx降低AP的机制仍不清楚。一种新兴的新理论
HTN可能会提供新的见解。据推测,HTN的部分原因是
肾神经、肾炎和HTN。这些发现表明,抗高血压反应
RDNx不是由于对肾功能本身的神经控制的破坏,而是由于阻断了
具有传出和传入肾神经的免疫细胞。
这些发现导致了这一提议的中心假设:DOCA-SALT HTN的部分原因是
促炎细胞因子在肾传入神经上的作用导致神经发生介导性HTN。
四个具体目标将严格检验这一中心假说。具体目标1:调查
细胞因子调节DOCA-SALT大鼠ARNA的神经生理机制。具体目标2:
确定免疫介质对DOCA-SALT大鼠ARNA调节作用的解剖学基础
还有老鼠。具体目标3:相互关联调节降压反应的血流动力学机制
DOCA-SALT HTN的ARNA消融及药理阻断对尿液中肾脏生物标志物的影响
发炎。特定目的4:使用一种新的GCaMP3小鼠体外肾脏切片制剂来鉴定
介导正常和DOCA-SALT小鼠肾传入神经细胞因子调节的分子靶点。
确定免疫细胞与肾传入神经相互作用的机制也将有助于HTN
有助于了解SNA升高的其他肾脏炎症性疾病,如慢性肾功能衰竭。
英文摘要
Abstract
Hypertension (HTN) is linked to increased sympathetic nervous system activity (SNA) and increased
activity of renal efferent nerves is thought to be important. However, the kidneys are also innervated by renal
afferent nerves, which project to central nervous system circuits that modulate SNA to various peripheral
targets. As such, increased afferent renal nerve activity (ARNA) is also postulated to contribute to increased
SNA and the pathogenesis of HTN. Renal denervation (RDNx) for treatment of HTN in humans is now
possible. However, the mechanisms by which RDNx lowers AP remain unknown. An emerging new theory of
HTN may provide new insights. It is hypothesized that HTN is caused, in part, by a close relationship between
renal nerves, renal inflammation, and HTN. These findings suggest that the antihypertensive response to
RDNx is not due to disruption of neural control of renal function per se, but rather, blockade of the interaction of
immune cells with efferent and afferent renal nerves.
These findings led to the Central Hypothesis of this proposal: DOCA-salt HTN is caused, in part, by
the action of proinflammatory cytokines on afferent renal nerves resulting in neurogenically mediated HTN.
Four Specific Aims will rigorously test this Central Hypothesis. Specific Aim 1: Investigate the
neurophysiological mechanisms by which cytokines modulate ARNA in the DOCA-salt rat. Specific Aim 2:
Define the anatomical substrates responsible for modulation of ARNA by immune mediators in DOCA-salt rats
and mice. Specific Aim 3: Correlate the hemodynamic mechanisms mediating the anti-hypertensive response
to ablation and pharmacological blockade of ARNA in DOCA-salt HTN, to urinary biomarkers of renal
inflammation. Specific Aim 4: Employ a novel GCaMP3 mouse ex vivo renal slice preparation to identify
molecular targets mediating cytokine modulation of afferent renal nerves in normal and DOCA-salt mice.
Identification of the mechanisms by which immune cells interact with renal afferent nerves in HTN will also
benefit understanding other renal inflammatory diseases with elevated SNA such as chronic renal failure.
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Renal nerves: time for reassessment of their role in hypertension?
肾神经:是时候重新评估其在高血压中的作用了?
DOI:
10.1093/ajh/hpu096
发表时间:
2014
期刊:
American journal of hypertension
影响因子:
3.2
作者:
[Fink,GregoryD, Osborn,JohnW]
通讯作者:
Osborn,JohnW
DOI:
10.1002/phy2.128
发表时间:
2013-10
期刊:
PHYSIOLOGICAL REPORTS
影响因子:
2.5
作者:
[Collister, John P, Olson, Marin K, Nahey, David B, Vieira, Alexandre A, Osborn, John W]
通讯作者:
Osborn, John W
DOI:
10.14814/phy2.13602
发表时间:
2018-03
期刊:
Physiological reports
影响因子:
2.5
作者:
[Foss JD, Fiege J, Shimizu Y, Collister JP, Mayerhofer T, Wood L, Osborn JW]
通讯作者:
Osborn JW
DOI:
10.1161/hypertensionaha.113.02144
发表时间:
2014-03
期刊:
Hypertension
影响因子:
8.3
作者:
[M. Schlaich;M. Esler;G. Fink;J. Osborn;D. Euler]
通讯作者:
M. Schlaich;M. Esler;G. Fink;J. Osborn;D. Euler
Reply from V. A. Averina, H. G. Othmer, G. D. Fink and J. W. Osborn.
V. A. Averina、H. G. Othmer、G. D. Fink 和 J. W. Osborn 的答复。
DOI:
10.1113/jphysiol.2013.254607
发表时间:
2013
期刊:
The Journal of physiology
影响因子:
--
作者:
[Averina,ViktoriaA, Othmer,HansG, Fink,GregoryD, Osborn,JohnW]
通讯作者:
Osborn,JohnW
共 6 条
Administrative Core
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批准号:10709633
-
项目类别:
-
资助金额:$22.33万
-
财政年份:2022
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负责人:John W Osborn
-
依托单位:
Administrative Core
-
批准号:10610557
-
项目类别:
-
资助金额:$25.26万
-
财政年份:2022
-
负责人:John W Osborn
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依托单位:
Structural and functional neurobiology of renal nerves: A platform for neuromodulation of renal function
-
批准号:9770836
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项目类别:
-
资助金额:$35.89万
-
财政年份:2017
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负责人:John W Osborn
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依托单位:
Targeted sympathetic ablation for treatment of hypertension
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批准号:8786097
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项目类别:
-
资助金额:$46.26万
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财政年份:2013
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负责人:John W Osborn
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依托单位:
Targeted sympathetic ablation for treatment of hypertension
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批准号:8962159
-
项目类别:
-
资助金额:$47.02万
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财政年份:2013
-
负责人:John W Osborn
-
依托单位:
Afferent renal nerves, renal inflammation, and hypertension
-
批准号:10064025
-
项目类别:
-
资助金额:$51.12万
-
财政年份:2013
-
负责人:John W Osborn
-
依托单位:
Targeted Sympathetic Ablation for Treatment of Hypertension
-
批准号:9187039
-
项目类别:
-
资助金额:$47.07万
-
财政年份:2013
-
负责人:John W Osborn
-
依托单位:
Long-Term Neural Determinants of Cardiovascular Diseases
-
批准号:7152860
-
项目类别:
-
资助金额:$108.52万
-
财政年份:2004
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负责人:John W Osborn
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依托单位:
Long-Term Neural Determinants of Cardiovascular Diseases
-
批准号:7539159
-
项目类别:
-
资助金额:$115.41万
-
财政年份:2004
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负责人:John W Osborn
-
依托单位:
Long-Term Neural Determinants of Cardiovascular Diseases
-
批准号:7326827
-
项目类别:
-
资助金额:$112.19万
-
财政年份:2004
-
负责人:John W Osborn
-
依托单位:
Long-Term Neural Determinants of Cardiovascular Diseases
-
批准号:6865132
-
项目类别:
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资助金额:$116.03万
-
财政年份:2004
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负责人:John W Osborn
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依托单位:
Long-Term Neural Determinants of Cardiovascular Diseases
-
批准号:6992769
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项目类别:
-
资助金额:$110.82万
-
财政年份:2004
-
负责人:John W Osborn
-
依托单位:
NPY,Neurovascular Niches and Stress-Induced Remodeling of Adipose Tissue
-
批准号:8586270
-
项目类别:
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资助金额:$38.34万
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财政年份:2001
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负责人:John W Osborn
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依托单位:
NPY,Neurovascular Niches and Stress-Induced Remodeling of Adipose Tissue
-
批准号:8391273
-
项目类别:
-
资助金额:$38.2万
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财政年份:2001
-
负责人:John W Osborn
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依托单位:
NPY,Neurovascular Niches and Stress-Induced Remodeling of Adipose Tissue
-
批准号:8122125
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项目类别:
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资助金额:$39.82万
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财政年份:2001
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负责人:John W Osborn
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依托单位:
NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL
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批准号:6390606
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项目类别:
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资助金额:$26.87万
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财政年份:2000
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负责人:John W Osborn
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依托单位:
NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL
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批准号:6603916
-
项目类别:
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资助金额:$29.7万
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财政年份:2000
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负责人:John W Osborn
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依托单位:
NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL
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批准号:6200218
-
项目类别:
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资助金额:$25.41万
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财政年份:2000
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负责人:John W Osborn
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依托单位:
NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL
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批准号:6527297
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项目类别:
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资助金额:$26.65万
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财政年份:2000
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负责人:John W Osborn
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依托单位:
Neural Mechanisms of Lone-Term Cardiovascular Control
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批准号:7095133
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项目类别:
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资助金额:$32.63万
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财政年份:1999
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负责人:John W Osborn
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依托单位:
海外基金