title: Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory.
abstract: Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with (5/6) renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT(1) receptor (AT(1)R); 2) the renoprotective and antiinflammatory effects of an association between the AT(1)R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nx(pre)). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: Nx(V) (vehicle), Nx(Los) (Los), Nx(NOF) (NOF), and Nx(Los/NOF) (Los/NOF). Nx(pre) rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT(1)R distribution shifted from mostly tubular in S to predominantly interstitial in Nx(pre). All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT(1)R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT(1)R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.
authors.affiliation: Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Anderson Ricardo Roman
authors.initials: AR
authors.lastname: Gonçalves
authors.forename: Clarice Kazue
authors.initials: CK
authors.lastname: Fujihara
authors.forename: Ana Lúcia
authors.initials: AL
authors.lastname: Mattar
authors.forename: Denise Maria Avancini Costa
authors.initials: DM
authors.lastname: Malheiros
authors.forename: Irene de Lourdes
authors.initials: Ide L
authors.lastname: Noronha
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Nucci
authors.forename: Roberto
authors.initials: R
authors.lastname: Zatz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004359:Drug Therapy, Combination; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009392:Nephrectomy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D007527:Isoenzymes; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019808:Losartan