Renal allograft protection with losartan in Fisher→Lewis rats: Hemodynamics, macrophages, and cytokines

Abstract

Background. We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model. Methods. The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344→LEW rats (LOS, N = 9) versus vehicletreated F344→LEW controls (CON, N = 9). Results. U(prot) V rose progressively in CON (from 7.0 ± 2.9 to 41 ± 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 ± 0.6 to 9.4 ± 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (P(GC)) was increased in CON (71 ± 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 ± 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 ± 0.2% in LOS versus 4 ± 2% in CON rats (P < 0.05). Tubulo- interstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-β, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats. Conclusions. The renoprotective effects of losartan in F344→LEW rats were associated with lowered P(GC), inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344→LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.