Inflammatory response in an experimental model of ischemic acute renal failure. Role of renin-angiotensin system

MOLINAS, SARA M.; TRUMPER, LAURA; MONASTEROLO, LILIANA; CASATI, PAULA; ELÍAS, M. MÓNICA

Rio de Janeiro. Brasil

Congreso; World Congress of Nephrology 2007; 2007

International Society of Nephrology

Inflammatory response in an experimental model of ischemic acute renal failure. Role of renin-angiotensin system Molinas, Sara1; Trumper, Laura2; Monasterolo, Liliana1; Casati, Paula1; Elías, M. Mónica1. Farmacología. Departamento de Ciencias Fisiológicas. Facultad Ciencias Bioquímicas y Farmacéuticas. Universidad Nacional de Rosario, Argentina. 1CONICET. 2CIUNR. World Congress of Nephrology 2007. Del 21 al 25 de abril de 2007. Rio de Janeiro. Brasil. Renin-angiotensin system (RAS) participates in the pathogenesis of several renal diseases. Angiotensin II (AGII), via AT1 receptor, mediates vasoactive and proinflammatory actions. Many authors have described RAS induction after renal ischemic-reperfusion injury (IRI), but the role of AT1 in the pathophysiology of renal IRI remains unclear. In our laboratory, we described that AT1 receptor antagonist, losartan, attenuated renal dysfunction caused by IRI. The aim of this work was to study the effects of renal IRI on the expression of RAS (AT1 and renin) and proinflammatory cytokines genes; and to evaluate the effect of AT1 blockade on the inflammatory response observed during IRI. Male Wistar rats were submitted to 40 minutes of unilateral renal ischemia followed by 24 hours of reperfusion (IR, n=6). Another group received losartan (Roemmers, 80 mg/kg/day, i.p.) during 3 days previous to ischemic insult (IRL, n=6). Control animals were submitted to sham operation (C, n=6) and another control group was pretreated with losartan (CL, n=6). We evaluated cortical AT1 and renin mRNA levels in IR by Real-Time PCR. Extravasation of Evans Blue dye into the kidney was used to estimate vascular permeability. Neutrophil accumulation was measured by assaying myeloperoxidase (MPO) activity in cortex and medulla, and mRNA levels of the proinflammatory cytokines TNF-a, IL-1b and IL-6 were determined by semiquantitative RT-PCR. Data were analysed using ANOVA followed by Newman-Keuls contrast. Cortical AT1 and renin mRNA expression were downregulated in IR when compared with C. IR kidneys showed higher vascular permeability than C (C= 51±3; IR= 100±8* mg Evans Blue/g dry tissue, *p<0.05 vs C) and MPO activity (cortex: C=1.2±0.1, IR=3.2±0.4*, medulla: C=0.6±0.1, IR=3.2±0.5* U/g tissue, *p<0.05 vs C). IR group presented increased mRNA levels of TNF-a, IL-1b and IL-6 in cortex and medulla. In control group, losartan pretreatment (CL) showed no changes in any of the parameters studied when compared with untreated rats (C). Losartan pretreatment (IRL) prevented the increase in MPO activity and TNF-a, IL-1b and IL-6 mRNA levels observed in IR cortex and medulla, but failed to prevent the vascular permeability increment. Downregulation of AT1 and renin gene expression could be due to the negative feedback that occurs after RAS activation. AGII, via AT1, would play a key role in neutrophil infiltration and induction of proinflammatory cytokines, but not in the alteration of renal vascular permeability induced by IRI, at least in these studied conditions. The anti-inflammatory actions of losartan could contribute to the previously observed protective effects of this drug against renal dysfunction caused by IRI.