A Role of T-Lymphocyte β-Arrestins in Hypertension
Authors: Ghobrial Mina , Fekete Eva M. , Muskus Patricia C. , Brozoski Daniel T. , Lu Ko-Ting , Guixa Ana Hantke , Wackman Kelsey K. 
Published: May 2024

The adaptive immune system and T-cells play a central role in the development of essential hypertension. The renin-angiotensin system regulates blood pressure (BP) through multiple mechanisms including effects on the immune system. Among several G-protein coupled receptors (GPCR) that regulate T-cell function, it has been hypothesized that specific T-cell populations use the angiotensin receptor (AT1R) to modulate immune responses in hypertension. Selective ablation of AT1R in T-cells paradoxically increases hypertensive end-organ damage (EOD). While AT1R typically induces the classical G protein signaling, recent studies have uncovered an alternative protective signaling-cascade at this receptor via β-Arrestin ( ARRB) proteins. Thus, we hypothesized that ARRB in T-lymphocytes mediates an anti-hypertensive and anti-inflammatory role in response to angiotensin II (ANG II) thereby decreasing EOD in hypertension. Transgenic mice with T-lymphocyte-specific knock outs of the Arrb1 gene were developed using a CD4-Cre x Arrb1-Flox system. Hypertensive conditions were modeled with a 3-pronged approach designed to induce kidney damage consisting of unilateral nephrectomy (UNX), maintenance on a 4% salt diet, and a continuous infusion of ANG II (1,000 ng/kg/min). Age and sex-matched Cre negative x Arrb1-Flox littermates were used as controls. BP was measured at baseline before and after UNX, and for the following three weeks using radiotelemetry. Inflammation was assessed using quantitative PCR (q-PCR). Preliminary data suggest that loss of T-cell specific Arrb1 is protective against ANG II-induced hypertension. At baseline CD4Arrb1-null and CD4Arrb1-WT mice had similar systolic BP (123.0±2.9 mmHg and 119.6±2.3 mmHg, respectively, n=5-7). However, CD4Arrb1-null mice exhibited an attenuated response to ANG II infusion after three weeks (162.5±11.8 mmHg vs 187.0±5.9 mmHg n=3-5; p = 0.03). After 15 days of ANG II, mice were placed in metabolic cages and urine was collected. In a 24-hour period, CD4Arrb1-null mice excreted significantly more sodium (1.98±0.07 mg/24hrs vs 1.66±0.03 mg/24hrs, n=3-4; p = 0.01). Tissue collected from the renal cortex following three weeks of ANG II infusion was analyzed for inflammatory cytokines using q-PCR. Gene expression was normalized to 18s expression in CD4Arrb1-WT mice under sham experimental conditions. Expression of tumor necrosis factor α (TNF-α) transcripts was attenuated in CD4Arrb1-null mice when compared to CD4Arrb1-WT (1.62±0.24-fold increase vs 0.67±0.07-fold decrease, respectively, n=3-4; p=0.006). Contrary to our hypothesis, these preliminary data suggest that T-cell Arrb1 does not protect against hypertensive or inflammatory responses to ANG II. However, these studies highlight the role of β-arrestin-1 proteins endogenous to T-lymphocytes in the modulation of the hypertensive response to ANG II.

Supported by grants from the AHA and NIH.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.