Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity
脂肪源性 sPRR 通过抑制肾 NCC 活性来控制血压的昼夜节律
基本信息
- 批准号:10522511
- 负责人:
- 金额:$ 63.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAgonistBlood PressureCardiovascular DiseasesCardiovascular systemCircadian DysregulationCircadian RhythmsCommunicationDataDiseaseDistal convoluted renal tubule structureDiurnal RhythmExcretory functionExhibitsHistidineImpairmentIn VitroKidneyMediatingMetabolicModelingMusMutagenesisNephronsNocturnal HypertensionObese MiceOrganPPAR gammaPeriodicityPhenotypePhosphoric Monoester HydrolasesProtein DephosphorylationReceptor SignalingRenal functionRoleSignal PathwaySiteSourceSurrogate MarkersTestingType 2 Angiotensin II ReceptorVariantblood pressure regulationcardiovascular risk factorcircadiancircadian regulationdiet-induced obesityhypertensiveimprovedin vitro activityin vivonovelreceptorreceptor function
项目摘要
Summary
Blood pressure (BP) and renal Na+ excretion exhibit diurnal rhythms and dysregulation of these rhythms leads
to nocturnal hypertension, a strong predictor of cardiovascular disease and target organ damage. Multiple Na+
transporters along the nephron are under the control of circadian regulation. In particular, renal abundance of
phosphorylated NaCl cotransporter (p-NCC), a surrogate marker of activated NCC, exhibits robust
rhythmicity in the kidney whereas total NCC (t-NCC) abundance remains constant. Disruption of p-NCC
rhythmicity is associated with impaired circadian rhythm of BP. Preliminary results showed that adipose-
derived soluble (pro)rein receptor (sPRR) functions as a key regulator of circadian rhythm of BP via
angiotensin type 2 receptor (AT2R)-dependent dephosphorylation of NCC. In this regard, adipose-specific
deletion of PRR or its upstream regulator PPARγ remarkably suppressed circadian rhythms of BP
accompanied with suppressed release of soluble PRR (sPRR). The circadian phenotype was recapitulated by
mutagenesis of the cleavage site of PRR. Supplement of sPRR-His, the histidine-tagged sPRR in these models
was able to restore circadian variations of BP accompanied with improved rhythms in p-NCC. In vitro data
demonstrated that sPRR-His directly reduced abundance of p-NCC but not t-NCC associated with elevated
phosphatase activity. Further intriguing in vitro and in vivo evidence suggests that sPRR directly interacted
with AT2R to control circadian rhythms of BP and p-NCC. Therefore, we hypothesize that PPARγ-driven
adipose-derived sPRR acts via AT2R to dephosphorylate NCC to control circadian rhythm of BP. To test this
hypothesis, first, we propose to define adipose tissue as a major source of circulating sPRR during circadian
regulation of BP and renal function. Second, we will test whether sPRR signals via AT2R in distal convoluted
tubule to activate a specific phosphatase to dephosphorylate NCC. Lastly, we will explore the role of sPRR-
His and AT2R agonist C21 as novel chronotherapeutic agents in diet-induced obesity mice. New information
resulted from this proposal will help define sPRR-mediated communication between adipose tissue and
kidneys in regulation of circadian rhythm of BP.
总结
血压(BP)和肾脏Na+排泄表现出昼夜节律,这些节律的失调导致
夜间高血压是心血管疾病和靶器官损害的有力预测因素。多重Na+
沿着肾单位的转运蛋白受昼夜节律调节的控制。特别是,肾脏中
磷酸化NaCl协同转运蛋白(p-NCC)是活化NCC的替代标记物,
在肾脏中的节律性,而总NCC(t-NCC)丰度保持恒定。p-NCC破坏
节律性与BP的昼夜节律受损有关。初步结果显示,脂肪-
衍生的可溶性(原)释放素受体(sPRR)作为血压昼夜节律的关键调节因子,
血管紧张素2型受体(AT 2 R)依赖性NCC去磷酸化。在这方面,脂肪特异性
PRR或其上游调节因子PPARγ的缺失可显著抑制血压的昼夜节律
伴随可溶性PRR(sPRR)的抑制释放。昼夜节律表型被概括为
PRR切割位点的突变。补充sPRR-His,这些模型中的组氨酸标记的sPRR
能够恢复血压的昼夜变化,同时改善p-NCC的节律。体外数据
结果表明,sPRR-His直接降低了p-NCC的丰度,但不降低与升高相关的t-NCC的丰度。
磷酸酶活性进一步有趣的体外和体内证据表明,sPRR直接相互作用
与AT 2 R一起控制BP和p-NCC的昼夜节律。因此,我们假设,
脂肪来源的sPRR通过AT 2 R使NCC去磷酸化以控制BP的昼夜节律。为了验证这一
假设,首先,我们建议将脂肪组织定义为昼夜节律期间循环sPRR的主要来源,
调节血压和肾功能。第二,我们将测试sPRR信号是否通过AT 2 R在远端回旋
微管激活特定的磷酸酶去磷酸化NCC。最后,我们将探讨sPRR的作用-
His和AT 2 R激动剂C21作为饮食诱导的肥胖小鼠的新型计时剂新信息
这一提议的结果将有助于定义脂肪组织和
肾脏对血压昼夜节律的调节。
项目成果
期刊论文数量(0)
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Tianxin Yang其他文献
Tianxin Yang的其他文献
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{{ truncateString('Tianxin Yang', 18)}}的其他基金
Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity
脂肪源性 sPRR 通过抑制肾 NCC 活性来控制血压的昼夜节律
- 批准号:
10636885 - 财政年份:2022
- 资助金额:
$ 63.07万 - 项目类别:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
盐敏感性高血压肾 S1P/sPRR/AT1R 通路的定义
- 批准号:
10293534 - 财政年份:2020
- 资助金额:
$ 63.07万 - 项目类别:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
盐敏感性高血压肾 S1P/sPRR/AT1R 通路的定义
- 批准号:
10514577 - 财政年份:2020
- 资助金额:
$ 63.07万 - 项目类别:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
盐敏感性高血压肾 S1P/sPRR/AT1R 通路的定义
- 批准号:
9888044 - 财政年份:2020
- 资助金额:
$ 63.07万 - 项目类别:
Role of (pro)renin receptor in aldosterone signaling in the kidney
肾素(原)受体在肾脏醛固酮信号传导中的作用
- 批准号:
9921471 - 财政年份:2018
- 资助金额:
$ 63.07万 - 项目类别:
Interaction of (pro)renin receptor and PPARy in regulation of plasma volume
肾素(原)受体和 PPARγ 在血浆容量调节中的相互作用
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9729034 - 财政年份:2017
- 资助金额:
$ 63.07万 - 项目类别:
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