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

Background. We sought to assess the effects of angiotensin receptor blockad e on glomerular hypertension, macrophage recruitment, and cytokine expressi on, all of which contribute to the development of chronic graft injury in t his model. Methods. The effects of treatment with the specific angiotensin II type 1 ( AT(1)) receptor antagonist, losartan, were assessed over 24 weeks in F344-- >LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9). Results. UprotV 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 increas ed 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). Tubulointerstitial in jury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte c hemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, indu cible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppres sed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 stainin g 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 an d recruitment, and suppression of macrophage-associated cytokines at 20 wee ks. 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-as sociated cytokines.