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Sex‐specific actions of the Prostaglandin E type 4 (EP4) receptor to attenuate salt sensitivity and hypertension
Author(s) -
Herrera Marcela,
Koller Beverly,
Coffman Thomas M
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1113.2
Subject(s) - medicine , endocrinology , renin–angiotensin system , vasodilation , macula densa , receptor , kidney , prostaglandin , prostanoid , conditional gene knockout , stimulation , angiotensin ii , furosemide , prostaglandin e2 , blood pressure , biology , biochemistry , gene , phenotype
Prostaglandin E2 (PGE2) is the major prostanoid produced by the kidney, mediating its actions via four distinct E‐prostanoid receptor isoforms: EP1‐EP4. The EP4 receptor (EP4R) induces closure of the ductus arteriosus (DA) and triggers macula densa stimulation of renin, but can also induce vasodilation. Thus, the net impact of the EP4R on BP regulation is not clear. Deletion of EP4R causes post‐natal lethality due to failure of DA closure. Therefore, conditional deletion of the EP4R was carried out by crossing EP4flox/flox mice with a mouse line bearing a Cre‐recombinase transgene with tamoxifen‐inducible expression in all tissues. After 2 weeks of tamoxifen induction, efficient excision of the EP4R was documented in kidney, aorta and spleen. Using radiotelemetry in male mice, we found that EP4R deletion increased resting BP by 5±1mm Hg (p<0.001), caused an exaggerated response to high salt feeding (118±1 vs. 108±1mmHg; p<0.001), and enhanced the severity of angiotensin II‐dependent hypertension (149±1 vs. 133±1mmHg; p<0.001). These BP differences were not apparent in female mice. We conclude that the actions of PGE2 to attenuate salt‐sensitivity and hypertension are mediated by EP4Rs. However, their impact on blood pressure differs between sexes. Source of research support: K99HL109167 (to MH) and R01 DK069896 (to TMC).