title: Vascular Smooth Muscle-Specific EP4 Receptor Deletion in Mice Exacerbates Angiotensin II-Induced Renal Injury.
abstract: Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs is contraindicated in hypertension, as it may reduce glomerular filtration rate (GFR) and renal blood flow. However, the identity of the specific eicosanoid and receptor underlying these effects is not known. We hypothesized that vascular smooth muscle prostaglandin E2 (PGE2) E-prostanoid 4 (EP4) receptor deletion predisposes to renal injury via unchecked vasoconstrictive actions of angiotensin II (AngII) in a hypertension model. Mice with inducible vascular smooth muscle cell (VSMC)-specific EP4 receptor deletion were generated and subjected to AngII-induced hypertension.
  
  
  
  EP4 deletion was verified by PCR of aorta and renal vessels, as well as functionally by loss of PGE2-mediated mesenteric artery relaxation. Both AngII-treated groups became similarly hypertensive, whereas albuminuria, foot process effacement, and renal hypertrophy were exacerbated in AngII-treated EP4VSMC-/-but not in EP4VSMC+/+mice and were associated with glomerular scarring, tubulointerstitial injury, and reduced GFR. AngII-treated EP4VSMC-/-mice exhibited capillary damage and reduced renal perfusion as measured by fluorescent bead microangiography and magnetic resonance imaging, respectively. NADPH oxidase 2 (Nox2) expression was significantly elevated in AngII-treated EP4-/-mice. EP4-receptor silencing in primary VSMCs abolished PGE2 inhibition of AngII-induced Nox2 mRNA and superoxide production.
  
  
  
  These data suggest that vascular EP4 receptors buffer the actions of AngII on renal hemodynamics and oxidative injury.
  
  
  
  EP4 agonists may, therefore, protect against hypertension-associated kidney damage. Antioxid. Redox Signal. 25, 642-656.
authors.affiliation: 1 Chronic Disease Program, Department of Medicine, Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario, Canada .|2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Thibodeau
authors.affiliation: 1 Chronic Disease Program, Department of Medicine, Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario, Canada .
authors.forename: Chet E
authors.initials: CE
authors.lastname: Holterman
authors.affiliation: 1 Chronic Disease Program, Department of Medicine, Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario, Canada .
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: 2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Anthony
authors.initials: A
authors.lastname: Carter
authors.affiliation: 3 The Ottawa Hospital , Ottawa, Ontario, Canada .
authors.forename: Gregory O
authors.initials: GO
authors.lastname: Cron
authors.affiliation: 1 Chronic Disease Program, Department of Medicine, Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario, Canada .|2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Boisvert
authors.affiliation: 2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Khaled S
authors.initials: KS
authors.lastname: Abd-Elrahman
authors.affiliation: 2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Karolynn J
authors.initials: KJ
authors.lastname: Hsu
authors.affiliation: 2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
authors.affiliation: 1 Chronic Disease Program, Department of Medicine, Kidney Research Centre, The Ottawa Hospital , Ottawa, Ontario, Canada .|2 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa , Ontario, Canada .|3 The Ottawa Hospital , Ottawa, Ontario, Canada .
authors.forename: Christopher R J
authors.initials: CR
authors.lastname: Kennedy
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000235:genetics*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics*; D012079:Renal Circulation / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000804:Angiotensin II; D015232:Dinoprostone
keywords: NADPH oxidase; PTGER4; angiotensin; hypertension