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
• 负责人: Tianxin Yang
• 金额: $ 58.66万
• 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/10636885
• 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; Phosphorylation; 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; symporter

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.

概括 血压 (BP) 和肾 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伤的有力预测因子。 沿着肾单位的转运蛋白受到昼夜节律调节的控制，特别是肾脏丰度。 磷酸化 NaCl 协同转运蛋白 (p-NCC) 是激活的 NCC 的替代标记，表现出强大的 肾脏的节律性，而总 NCC (t-NCC) 丰度保持不变。 节律性与血压昼夜节律受损有关。初步结果表明，脂肪- 衍生的可溶性 (pro)rein 受体 (sPRR) 通过以下方式发挥血压昼夜节律的关键调节作用： 血管紧张素 2 型受体 (AT2R) 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的缺失显着抑制了BP的昼夜节律 伴随着可溶性 PRR (sPRR) 的释放受到抑制。 PRR 切割位点的突变 sPRR-His 的补充，这些模型中带有组氨酸标签的 sPRR。 能够恢复血压的昼夜节律变化，并改善 p-NCC 体外数据的节律。 sPRR-His 证明 sPRR-His 直接降低 p-NCC 丰度，但不降低与升高相关的 t-NCC 丰度。 进一步有趣的体外和体内证据表明 sPRR 直接相互作用。 AT2R 来控制 BP 和 p-NCC 的昼夜节律，因此，我们采用 PPARγ 驱动。 脂肪源性 sPRR 通过 AT2R 使 NCC 去磷酸化，从而控制血压的昼夜节律。 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 其次，我们将测试 sPRR 是否通过远端回旋中的 AT2R 发出信号。 最后，我们将探讨 sPRR- 的作用。 His 和 AT2R 激动剂 C21 作为饮食诱导肥胖小鼠的新型时间治疗剂。 该提案的结果将有助于定义脂肪组织和脂肪组织之间 sPRR 介导的通讯 肾脏对血压昼夜节律的调节。