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

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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.