title: P2X(7) receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats.
abstract: The P2X(7) receptor is a ligand-gated ion channel activated by extracellular ATP, and a common genetic variation in the P2X(7) gene significantly affects blood pressure. P2X(7) receptor expression is associated with renal injury and some inflammatory diseases. Brilliant blue G (BBG) is a selective rat P2X(7) receptor antagonist. In this study, to test whether BBG has protective effects on salt-sensitive hypertension and renal injury, Dahl salt-sensitive (DS) rats fed an 8% NaCl diet were i.p. injected with BBG (50 mg kg(-1) per day) for 4 weeks. We also tested another P2X(7) receptor antagonist, namely A-438079 (100 mg kg(-1) per day), for 7 days. We found that P2X(7) antagonism markedly attenuated salt-sensitive hypertension, urinary protein or albumin excretion, renal interstitial fibrosis and macrophage and T-cell infiltration in the DS rats, and significantly improved creatinine clearance. In an in vitro experiment using macrophages, we showed that lipopolysaccharide (LPS)-primed macrophages from the DS rats released more interleukin-1 beta in response to BzATP, a P2X(7) receptor agonist, than the macrophages from Lewis rats, possibly due to higher P2X(7) expression in the DS rats. In conclusion, in vivo blockade of P2X(7) receptors attenuated salt-sensitive hypertension and renal injury in the DS rats. Thus, P2X(7) appears to be responsible for a vicious cycle of salt-sensitive hypertension and renal injury in the DS rats, through higher expression in the immune cells. Furthermore, P2X(7) antagonists can prevent the development of salt-sensitive hypertension and renal injury, thus confirming that the P2X(7) receptor is an important therapeutic target.
authors.affiliation: Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Xu
authors.initials: X
authors.lastname: Ji
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Naito
authors.forename: Go
authors.initials: G
authors.lastname: Hirokawa
authors.forename: Huachun
authors.initials: H
authors.lastname: Weng
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hiura
authors.forename: Rie
authors.initials: R
authors.lastname: Takahashi
authors.forename: Naoharu
authors.initials: N
authors.lastname: Iwai
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents; D015153:Blotting, Western; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D000959:Antihypertensive Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate