Ischemic acute renal failure: Long-term histology of cell and matrix changes in the rat
Ischemic acute renal failure: Long-term histology of cell and matrix changes in the rat
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DOI：
10.1046/j.1523-1755.2000.00097.x
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发表时间：
2000-06-01
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;Hewitson, TD;Jones, CL
背景急性肾缺血和再灌注时伴随的细胞浸润和基质积聚是常见的，但定义不清。缺血的长期后果可能不可逆地损害肾脏。雌性Sprague-Dawley大鼠（200 g）接受单侧肾切除术。5天后，左肾蒂闭塞45分钟。在缺血后0、1、2、4、8、16、32、64和180天处死动物（N = 6）。免疫组化检测单核/巨噬细胞（Mo/M phi）、艾德-1（ED-1）、肌成纤维细胞（α-平滑肌肌动蛋白（α-SMA））、III型胶原、TV、基质金属蛋白酶-2（MMP-2）、增殖细胞核抗原（PCNA）及末端dUTP缺口末端标记（TUNEL）。缺血后动物的肾脏重量在所有时间点均增加（缺血后至对照组，第8天为1.47 +/- 0.21至0.94 +/- 0.12 g;第64天为1.49 +/- 0.20至1.27 +/- 0.13 g;第180天为1.86 +/- 0.1至1.24 +/- 0.2 g）。第2天血清肌酐值升高至0.42 +/- 0.10 mmol/L，但第8天恢复至对照水平（0.05 mmol/L）。肾小球IV型胶原蛋白从缺血后2天至16天下降，伴随着MMP-2的增加。在第8天，结节的面积分数最大（19.55 +/- 0.91%，而第0天为8.08 +/- 0.27%），在第180天观察到第二次增加（16.61 +/- 0.70%）。缺血后第2天至第8天，间质Mo/M phi增加（8.84 +/- 2.12至133.32 +/- 14.04/0.91 mm（2）），然后下降。肌成纤维细胞局部增殖（PCNA双标记），从第2天到第16天发现数量增加（第8天最大，26.96 +/-3.04%，与第0天相比，0.88 +/- 0.11%）。在缺血后组中，IV型胶原增加至第8天（20.84 +/- 1.30%），但随后在第64天降至低于对照值（2.22 +/- 0.15%），然后在第180天恢复正常。间质胶原III增加至第8天（0.45 +/- 0.07%至2.55 +/- 0.36%），然后在第32天降低至对照水平，但在第64天和第180天显著增加至约6%。细胞增殖（PCNA）在第2天和第4天最大（影响肾小管细胞和肌成纤维细胞，但不影响巨噬细胞）。在缺血后第8天，间质细胞和肾小管细胞凋亡最多。在缺血性急性肾功能衰竭模型中，发现Mo/M phi、MF和IV型胶原积累的显著变化。功能和结构变化的可逆性与进展性疾病中发现的可逆性形成鲜明对比。在缺血后64天和180天观察到的III型胶原增加表明，从长远来看，可能会观察到进一步的慢性结构变化。
Background. The cellular infiltration and matrix accumulation accompanying acute renal ischemia and reperfusion have been frequently noted but poorly defined. The long-term consequences of ischemia may irreversibly damage the kidney.Methods. Female Sprague-Dawley rats (200 g) underwent unilateral nephrectomy. After five days, the left renal pedicle was occluded for 45 minutes. Animals were sacrificed at 0, 1, 2, 4, 8, 16, 32, 64, and 180 days postischemia (N = 6). Immunohistochemistry for monocytes/macrophages (Mo/M phi, ED-1), myofibroblasts [alpha-smooth muscle actin (alpha-SMA)], collagen III and TV, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antigen (PCNA) and terminal dUTP nick end labeling (TUNEL) were performed.Results. Kidney weights of postischemic animals were increased at all time points (postischemic to controls, 1.47 +/- 0.21 to 0.94 +/- 0.12 g at day 8; 1.49 +/- 0.20 to 1.27 +/- 0.13 g at day 64; and 1.86 +/- 0.1 to 1.24 +/- 0.2 g at day 180). Serum creatinine values increased to 0.42 +/- 0.10 mmol/L at day 2 but returned to control levels by day 8 (0.05 mmol/L). Glomerular collagen IV was decreased from 2 to 16 days postischemia, which was accompanied by an increase in MMP-2. The fractional area of the interstitium was greatest at day 8 (19.55 +/- 0.91% compared with day 0 at 8.08 +/- 0.27%), with a second increase observed at day 180 (16.61 +/- 0.70%). Interstitial Mo/M phi increased postischemia from days 2 through 8 (8.84 +/- 2.12 to 133.32 +/- 14.04 per 0.91 mm(2)) and then decreased. Myofibroblasts proliferated locally (PCNA double labeling was demonstrated), and increased numbers were found from days 2 through 16 (maximal at day 8, 26.96 +/- 3.04%, compared with day 0, 0.88 +/- 0.11%). In the postischemic groups, collagen IV increased to day 8 (20.84 +/- 1.30%), but then decreased to below control values at day 64 (2.22 +/- 0.15%) before returning to normal by day 180. Interstitial collagen III increased to 8 days (0.45 +/- 0.07% to 2.55 +/- 0.36%) and then decreased to control levels by day 32, but showed a marked increase to approximately 6% at days 64 and 180. Cellular proliferation (PCNA) was maximal at days 2 and 4 (affecting tubule cells and myofibroblasts but not macrophages). Apoptosis was maximal at day 8 (in both interstitial and tubule cells) in the postischemic groups.Conclusion. Marked changes in the accumulation of Mo/M phi, MF, and collagen IV were found in this model of ischemic acute renal failure. The reversibility of functional and structural changes is in marked contrast to that found in progressive disease. The increases observed for collagen III at 64 and 180 days postischemia suggest that in the long term, however, further chronic structural changes may be observed.