title: Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension.
abstract: In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.
authors.affiliation: Cardiovascular Research, Physiology, University Zürich-Irchel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hermann
authors.forename: Sidney
authors.initials: S
authors.lastname: Shaw
authors.forename: Eva
authors.initials: E
authors.lastname: Kiss
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camici
authors.forename: Nico
authors.initials: N
authors.lastname: Bühler
authors.forename: Remy
authors.initials: R
authors.lastname: Chenevard
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D000068579:Celecoxib; D002452:Cell Count; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D007783:Lactones / Q000494:pharmacology; D009000:Monocytes / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D012965:Sodium Chloride; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D012965:Sodium Chloride; D002097:C-Reactive Protein; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib