TY - JOUR
T1 - Renal allograft protection with losartan in Fisher→Lewis rats
T2 - Hemodynamics, macrophages, and cytokines
AU - Ziai, Farzad
AU - Nagano, Hiroaki
AU - Kusaka, Mamoru
AU - Coito, Ana J.
AU - Troy, Julia L.
AU - Nadeau, Kari C.
AU - Rennke, Helmut G.
AU - Tilney, Nicholas L.
AU - Brenner, Barry M.
AU - Mackenzie, Harald S.
N1 - Funding Information:
This work was supported by U.S. Public Health Service grant 9 P01 DK 46190-23 and with funds from Merck Research Laboratories, who also supplied the losartan. F.Z. is the recipient of a Shroedinger Award from the Austrian Science Foundation. H.S.M. was the recipient of a grant from Baxter Healthcare Renal Division. Portions of this work were published in abstract form ( J Am Soc Nephrol 8:670A, 1997).
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034117224&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034117224&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2000.00122.x
DO - 10.1046/j.1523-1755.2000.00122.x
M3 - Article
C2 - 10844632
AN - SCOPUS:0034117224
SN - 0085-2538
VL - 57
SP - 2618
EP - 2625
JO - Kidney International
JF - Kidney International
IS - 6
ER -