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Characterization of Dahl salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension. Purinergic Signal 2015 Dec;11(4):519-31 PMID: 26385692 PMCID: PMC4648794

Pubmed ID

26385692

DOI

10.1007/s11302-015-9470-7

Abstract

The A(2B) adenosine receptor (AR) has emerged as a unique member of the AR family with contrasting roles during acute and chronic disease states. We utilized zinc-finger nuclease technology to create A(2B)AR gene (Adora2b)-disrupted rats on the Dahl salt-sensitive (SS) genetic background. This strategy yielded a rat strain (SS-Adora2b mutant rats) with a 162-base pair in-frame deletion of Adora2b that included the start codon. Disruption of A(2B)AR function in SS-Adora2b mutant rats was confirmed by loss of agonist (BAY 60-6583 or NECA)-induced cAMP accumulation and loss of interleukin-6 release from isolated fibroblasts. In addition, BAY 60-6583 produced a dose-dependent increase in glucose mobilization that was absent in SS-Adora2b mutants. Upon initial characterization, SS-Adora2b mutant rats were found to exhibit increased body weight, a transient delay in glucose clearance, and reduced proinflammatory cytokine production following challenge with lipopolysaccharide (LPS). In addition, blood pressure was elevated to a greater extent (∼15-20 mmHg) in SS-Adora2b mutants as they aged from 7 to 21 weeks. In contrast, hypertension augmented by Ang II infusion was attenuated in SS-Adora2b mutant rats. Despite differences in blood pressure, indices of renal and cardiac injury were similar in SS-Adora2b mutants during Ang II-augmented hypertension. We have successfully created and validated a new animal model that will be valuable for investigating the biology of the A(2B)AR. Our data indicate varying roles for A(2B)AR signaling in regulating blood pressure in SS rats, playing both anti- and prohypertensive roles depending on the pathogenic mechanisms that contribute to blood pressure elevation.

Author List

Nayak S, Khan MA, Wan TC, Pei H, Linden J, Dwinell MR, Geurts AM, Imig JD, Auchampach JA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Melinda R. Dwinell PhD Center Associate Director, Associate Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
John D. Imig PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Md Abdul Hye Khan PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84947616348   5 Citations

MESH terms used to index this publication - Major topics in bold

Adenosine A2 Receptor Agonists
Aminopyridines
Animals
Blood Pressure
Cyclic AMP
Cytokines
Dose-Response Relationship, Drug
Fibroblasts
Hypertension
Interleukin-6
Mutation
Rats
Rats, Inbred Dahl
Receptor, Adenosine A2B
Signal Transduction
jenkins-FCD Prod-332 f92a19b0ec5e8e1eff783fac390ec127e367c2b5