Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists

Background. Endothelin (ET) may be a mediator of injury following ischemia- induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when admini stered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed. Methods. We investigated the use of ET, antagonists, PD 156707 (ETA) and SE 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The r ight kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minute s. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 1 56707 (N = 7) or SE 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three n ephrectomized groups that did not undergo ischemia but that received infusi ons of saline (N = 6), PD 156707 (N = 6), and SE 209670 (N = 6), respective ly, were also studied. Animals were sacrificed one week postischemia. Quant itation of monocytes and macrophages (Mo/M phi), alpha-smooth muscle actin- positive myofibroblasts, and collagens type III and IV was performed by imm unohistochemical staining. Cell kinetics were examined by staining for apop tosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen. Results. All ischemic groups of rats initially developed raised serum creat inine levels; however, no significant difference was observed between the g roups (Kruskal-Wallis). Creatinines returned to preischemic values in all g roups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/M phi was significantly reduced in groups treated with ETR antagonists ( P < 0.001). The presence of myofibroblasts was also significantly reduced i n the antagonist-treated groups (P < 0.001). This was also paralleled by re duced quantities of collagen IV in the treated rat groups (P < 0.001). The interstitial area was also significantly greater in the saline group (P < 0 .001). The amount of collagen III did not significantly differ between rat groups. Apoptosis was reduced (P < 0.001) by treatment with ETR antagonists , whereas proliferation was enhanced (P < 0.005). All non-ischemic groups s howed no variation in any parameter studied at this time point. Conclusions. Treatment of ischemic ARF in the rat with ETR antagonists PD 1 56707 and SE 209670 attenuated cellular infiltration and matrix accumulatio n. An advantage of one antagonist over the other could not be determined in this study. The marked discrepancy between function and pathology (former unchanged,latter markedly improved) may be due to the time frame of this ex periment, and longer outcome measures need to be assessed.