Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists
Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists
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DOI：
10.1046/j.1523-1755.1999.00253.x
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发表时间：
1999-01-01
影响因子：
19.6
通讯作者：
Jones, CL
中科院分区：
文献类型：
--
作者：
Forbes, JM;Leaker, B;Jones, CL
背景内皮素（ET）可能是缺血性急性肾功能衰竭（ARF）损伤的介质。ET受体（ETR）拮抗剂已被报道在大鼠肾后缺血-再灌注损伤时增加存活率和降低血清肌酐。肾细胞和细胞外基质对这种疗法的反应尚未解决。我们研究了ET拮抗剂PD 156707（ETA）和SE 209670（ETA和ETB）在亚致死性缺血后ARF治疗中的应用。切除体重约200 g的雌性Sprague-Dawley大鼠的右肾。5天后，左肾蒂闭塞45分钟。肾缺血后24小时，给予两种ETR拮抗剂PD 156707（N = 7）或SE 209670（N = 8）中的一种。将实验动物与仅接受盐水的缺血组（N = 9）进行比较。还研究了未经历缺血但分别接受盐水（N = 6）、PD 156707（N = 6）和SE 209670（N = 6）输注的三个肾切除组。缺血后一周处死动物。通过免疫组织化学染色定量单核细胞和巨噬细胞（Mo/M phi）、α-平滑肌肌动蛋白阳性肌成纤维细胞以及III型和IV型胶原。用末端脱氧尿苷三磷酸（dUTP）缺口末端标记法检测细胞凋亡，用增殖细胞核抗原检测细胞增殖。所有缺血组大鼠最初均出现血清肌酐水平升高;然而，未观察到组间存在显著差异（Kruskal-Wallis）。在处死时，所有组的肌酐均恢复至缺血前值。未发现组间肾脏重量或体重存在显著差异。组织学上，ETR拮抗剂治疗组Mo/M phi浸润明显减少（P < 0.001）。肌成纤维细胞的存在在拮抗剂治疗组中也显著减少（P < 0.001）。这也被治疗组中IV型胶原的量减少所抵消（P < 0.001）。生理盐水组的间质面积也明显大于对照组（P < 0.001）。三型胶原的量在大鼠组之间没有显著差异。用ETR拮抗剂处理后，细胞凋亡减少（P < 0.001），而增殖增加（P < 0.005）。所有非缺血组在此时间点研究的任何参数均无变化。用ETR拮抗剂PD 156707和SE 209670治疗大鼠缺血性ARF可减弱细胞浸润和基质蓄积。本研究中无法确定一种拮抗剂相对于另一种拮抗剂的优势。功能和病理学之间的显著差异（前者不变，后者明显改善）可能是由于本实验的时间范围，需要评估更长的结局指标。
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 administered 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 right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SE 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SE 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/M phi), alpha-smooth muscle actin-positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis 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 creatinine levels; however, no significant difference was observed between the groups (Kruskal-Wallis). Creatinines returned to preischemic values in all groups 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 in the antagonist-treated groups (P < 0.001). This was also paralleled by reduced 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 showed no variation in any parameter studied at this time point.Conclusions. Treatment of ischemic ARF in the rat with ETR antagonists PD 156707 and SE 209670 attenuated cellular infiltration and matrix accumulation. 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 experiment, and longer outcome measures need to be assessed.