Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity

摘要 血压和肾脏钠离子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强烈预测因素。多重钠离子 沿肾单位的转运蛋白受到昼夜节律的控制。尤其是，肾脏富集性 磷酸化的氯化钠共转运体(p-NCC)是激活的NCC的替代标志物，表现出很强的稳定性 肾脏的节律性，而总的NCC(t-NCC)丰度保持不变。P-NCC中断 节律性与血压昼夜节律受损有关。初步结果显示，脂肪- 衍生的可溶性(PRO)肾素受体(SPRR)是血压昼夜节律的关键调节因子。 血管紧张素2型受体(AT2R)依赖的NCC去磷酸化。在这方面，特定脂肪 PrR或其上游调节因子PPARγ的缺失显著抑制血压昼夜节律 并伴有可溶性PRR(SPRR)的抑制释放。昼夜节律表型概括如下 PRR裂解位点的诱变。补充sPRR-His，组氨酸标记的sPRR 能恢复p-NCC的血压昼夜节律变化并改善节律。体外数据 表明sPRR-His直接降低了p-NCC的丰度，但与t-NCC的升高无关 磷酸酶活性。更耐人寻味的体外和体内证据表明，sPRR直接相互作用 用AT2R控制血压和p-NCC的昼夜节律。因此，我们假设PPAR由γ驱动 脂肪来源的sPRR通过AT2R使NCC去磷酸化，从而控制血压昼夜节律。为了测试这一点 假设，首先，我们建议将脂肪组织定义为昼夜循环sPRR的主要来源。 调节血压和肾功能。其次，我们将测试sPRR信号是否通过AT2R在远端卷曲 激活一种特定的磷酸酶以使NCC脱磷的小管。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辰治疗药物。新信息 这一提议的结果将有助于定义sPRR介导的脂肪组织和 肾脏在血压昼夜节律调节中的作用。

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.