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: 10522511
• 负责人: Tianxin Yang
• 金额: $ 63.07万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10522511
• 关键词: Adipose tissue; Agonist; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Communication; Data; Disease; Distal convoluted renal tubule structure; Diurnal Rhythm; Excretory function; Exhibits; Histidine; Impairment; In Vitro; Kidney; Mediating; Metabolic; Modeling; Mus; Mutagenesis; Nephrons; Nocturnal Hypertension; Obese Mice; Organ; PPAR gamma; Periodicity; Phenotype; Phosphoric Monoester Hydrolases; Protein Dephosphorylation; Receptor Signaling; Renal function; Role; Signal Pathway; Site; Source; Surrogate Markers; Testing; Type 2 Angiotensin II Receptor; Variant; blood pressure regulation; cardiovascular risk factor; circadian; circadian regulation; diet-induced obesity; hypertensive; improved; in vitro activity; in vivo; novel; receptor; receptor function

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切割位点的诱变。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。