Truong L D, Petrusevska G, Yang G, Gurpinar T, Shappell S, Lechago J, Rouse D, Suki W N
Department of Pathology, Methodist Hospital, Houston, Texas, USA.
Kidney Int. 1996 Jul;50(1):200-7. doi: 10.1038/ki.1996.303.
Cell proliferation and apoptosis in kidneys with chronic obstructive uropathy (COU) have not been adequately studied. Whether these fundamental cellular processes play any role in the pathogenesis and evolution of COU remains undetermined. Sprague-Dawley rats with COU induced by unilateral ureteral ligation were sacrificed at postoperative days 1, 6, 9, 15, 34, 43, 60, 75, and 90, and were compared with control, sham-operated rats sacrificed at days 0, 15, 43, and 90. The kidneys with ureteral ligation, the contralateral kidneys, and the control kidneys were submitted to in situ end-labeling of fragmented DNAs for the detection of apoptotic cells, and to immunostaining with many monoclonal antibodies directed against the nuclear antigens associated with cell proliferation for the detection of proliferating cells. Additional rats with COU were also submitted to BrdU labeling to detect proliferating cells. The tubular, interstitial, and glomerular cells showing either apoptosis or proliferation were separately quantitated and the obtained data were correlated with dry kidney weight, tubular diameter, glomerular surface area and interstitial volume. Apoptotic tubular cells in kidney with COU increased rapidly, reaching 30-fold that of control at day 25, which was followed by an equally rapid decrease to the control level. During the same period, both the dry kidney weight and the mean tubular diameter decreased markedly. These data suggest that apoptosis may play a significant role in tubular atrophy and renal weight loss. The rapid increase in tubular cell apoptosis was immediately preceded by a 37% gain in the dry kidney weight over the control; just before that increase, there was also an approximate 60-fold increase in the proliferation rate of tubular cells detected by immunostaining for proliferating nuclear antigen or by BrdU labeling. The significance of this intriguing temporal relationship of tubular cell apoptosis and proliferation remains to be elucidated, but it may have pathogenetic implications. In contrast to the rise and fall of the frequency of tubular cell apoptosis and proliferation, the frequency of interstitial cell apoptosis and proliferation displayed continuous increase toward the end of the experiment, with a roughly parallel increase in the interstitial damage. Apoptosis and proliferation of glomerular cells in kidneys with COU did not show any significant changes throughout the experiment. In conclusion, the obtained data suggest that tubular cell apoptosis may be pathogenetically related to the tubular atrophy and renal tissue loss in COU, and that proliferation and apoptosis of interstitial cells may play a role in the observed interstitial changes in this model. This study should provide the impetus for further exploration of the mechanisms of cell death and cell proliferation as a novel venue for understanding the pathogenesis of COU.
慢性梗阻性尿路病（COU）肾脏中的细胞增殖和凋亡尚未得到充分研究。这些基本的细胞过程是否在COU的发病机制和演变中发挥任何作用仍未确定。将单侧输尿管结扎诱导COU的Sprague-Dawley大鼠在术后第1、6、9、15、34、43、60、75和90天处死，并与在第0、15、43和90天处死的对照假手术大鼠进行比较。将输尿管结扎侧肾脏、对侧肾脏和对照肾脏进行原位DNA片段末端标记以检测凋亡细胞，并用许多针对与细胞增殖相关的核抗原的单克隆抗体进行免疫染色以检测增殖细胞。另外的COU大鼠也进行BrdU标记以检测增殖细胞。分别对显示凋亡或增殖的肾小管、间质和肾小球细胞进行定量，并将获得的数据与肾脏干重、肾小管直径、肾小球表面积和间质体积相关联。COU肾脏中的凋亡肾小管细胞迅速增加，在第25天时达到对照的30倍，随后同样迅速下降至对照水平。在同一时期，肾脏干重和平均肾小管直径均明显下降。这些数据表明凋亡可能在肾小管萎缩和肾脏重量减轻中起重要作用。肾小管细胞凋亡的迅速增加之前，肾脏干重比对照增加了37%；就在该增加之前，通过增殖细胞核抗原免疫染色或BrdU标记检测到的肾小管细胞增殖率也增加了约60倍。这种有趣的肾小管细胞凋亡与增殖的时间关系的意义仍有待阐明，但可能具有发病机制方面的意义。与肾小管细胞凋亡和增殖频率的上升和下降相反，间质细胞凋亡和增殖频率在实验结束时持续增加，间质损伤也大致平行增加。COU肾脏中肾小球细胞的凋亡和增殖在整个实验过程中未显示任何显著变化。总之，获得的数据表明肾小管细胞凋亡可能在发病机制上与COU中的肾小管萎缩和肾组织丢失相关，并且间质细胞的增殖和凋亡可能在该模型中观察到的间质变化中起作用。本研究应为进一步探索细胞死亡和细胞增殖机制提供动力，作为理解COU发病机制的新途径。
