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1 Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, Sao Paulo, SP, Brazil
2 Department of Pharmacology, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
* To whom correspondence should be addressed. E-mail: rzatz{at}usp.br.
Chronic renal injury can be mediated by angiotensin II (AII) 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: a) the intrarenal distribution of COx-2, AII and the AT1 receptor (AT1R); b) the renoprotective and antiinflammatory effects of an association between the AT1R blocker, losartan (LOS) and the gastric sparing antiinflammatory, 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 (Group Nxpre). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: NxV (vehicle), NxLOS (LOS) NxNOF (NOF) and NxLOS/NOF (LOS/NOF). Nxpre rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion and macrophage infiltration, accompanied by abnormal glomerular, vascular and interstitial COx-2 expression. AII appeared in interstitial cells, in contrast with S, in which AII was virtually confined to afferent arterioles. Intrarenal AT1R distribution shifted from mostly tubular in S to predominantly interstitial in Nxpre. All these changes were aggravated at 120 days, and attenuated by LOS and NOF monotherapies. LOS/NOF treatment arrested renal structural injury and AII expression, and reversed hypertension, albuminuria and renal inflammation. In conclusion, abnormal expression of COx-2, AII and AT1R may be key to development of renal injury in Nx. Concomitant COx-2 inhibition and AT1Rblockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.
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