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

Background. We sought to assess the effects of angiotensin macrophages, and macrophage-associated cytokines. 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 angioten- Recent experimental and clinical evidence emphasizes sin II type 1 (AT1) receptor antagonist, losartan, were assessed contributions from both antigen-independent and antiover 24 weeks in F344!LEW rats (LOS, N 5 9) versus vehicletreated F344!LEW controls (CON, N 5 9). gen-dependent factors in the pathogenesis of chronic Results. UprotV rose progressively in CON (from 7.0 6 2.9 renal allograft failure [1‐6]. A growing body of data to 41 6 17 mg/day at 24 wk) but remained at baseline in LOS also implicates injury processes associated with extensive (4.2 6 0.6 to 9.4 6 1.3 mg/day, P , 0.05 vs. CON). Glomerular nephron loss as a significant determinant of progressive capillary pressure (PGC) was increased in CON (71 6 1m m graft injury in the F344!LEW rat model of late renal Hg at week 20), but remained within the normal range in LOS rats (54 6 2m m Hg,P , 0.05). Glomerulosclerosis averaged allograft failure. Increased glomerular capillary hydrau0.3 6 0.2% in LOS versus 4 6 2% in CON rats (P , 0.05). lic pressure ("PGC) [7‐9] and glomerular hyperfiltration Tubulointerstitial injury was minimal in both LOS and CON [8, 9] have been observed in F344!LEW rats, suggesting rats (1). The overexpression of renal cortical cytokine mRNA that chronic glomerular injury in this model is driven, levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleu- at least in part, by glomerular hemodynamic factors. kin-1, inducible nitric oxide synthase, and transforming growth Evidence supporting this view came from studies confactor-b, assessed by competitive reverse transcription-poly- ducted in our laboratories showing that restoring total merase chain reaction, was suppressed in LOS versus CON recipient kidney mass essentially normalized PGC and rats at 20 weeks. Macrophage and T-cell numbers were de