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

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $630,704

## Abstract

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.

## Key facts

- **NIH application ID:** 10522511
- **Project number:** 1R01HL160020-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Tianxin Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $630,704
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522511

## Citation

> US National Institutes of Health, RePORTER application 10522511, Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity (1R01HL160020-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522511. Licensed CC0.

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