Caulfield J P, Reid J J, Farquhar M G
Lab Invest. 1976 Jan;34(1):43-59.
The visceral glomerular epithelium of rats made nephrotic by daily injections of puromycin aminonucleoside was examined from the time of onset of proteinuria (day 6) to the time when many animals die (day 15) in order to establish the chronology of the pathologic alterations which occur during the course of the disease. In addition, the structure of the residual epithelial slits was examined using special fixatives and freeze-fracture. Changes seen early in the disease (7 to 9 days) are: (1) a reduction in the number of foot processes and filtration slits; (2) occurrence of occluding junctions in many of the residual slits coupled with displacement of the slit diaphragms; (3) thinning of the dense central portion of the basement membrane (lamina densa) with a corresponding widening of the space (lamina rara externa) between it and the epithelium; (4) heightened epithelial pinocytosis with increased numbers of protein absorption droplets or lysosomes. In freeze-fracture preparations the occluding junctions were seen to be limited in extent and made up of only a few strands, indicating they are incomplete and represent occluding maculae or fasciae rather than zonulae. Later on in the disease (10 to 15 days) no further changes in the number or arrangement of slits is evident, but other alterations occur: (1) denuded regions of basement membrane are seen where there is initially partial and eventually complete detachment of the epithelium from the basement membrane; (2) increasing numbers of large vacuoles or phagosomes and decreasing numbers of fully condensed lysosomes are present; and (3) basement membrane-like material is seen in the spaces between the partially detached epithelium and basement membrane. The new findings in this study are: (1) the clarification of early (reversible) versus late (probably irreversible) changes in the glomerular epithelium in a acute aminonucleoside nephrosis; (2) delineation of the structure of the residual epithelial slits; (3) the description of progressive loosening of the attachment between the epithelium and the basement membrane leading to focal or complete epithelial cell detachment; (4) the presentation of evidence indicating that exhaustion of the lysosomal system of the glomerular epithelium (in protein absorption and concentration) occurs late in the disease. The available evidence is summarized and indicates that the glomerular basement membrane, the main glomerular filter, is defective in aminonucleoside nephrosis and allows increased protein leakage. However, it seems likely that the main site of action of aminonucleoside is on the epithelium leading to the production of defective basement membrane.
为了确定肾病过程中发生的病理改变的时间顺序，对每日注射嘌呤霉素氨基核苷而导致肾病的大鼠的肾小球脏层上皮进行了检查，检查时间从蛋白尿出现时（第6天）到许多动物死亡时（第15天）。此外，使用特殊固定剂和冷冻断裂技术检查了残余上皮裂隙的结构。疾病早期（7至9天）出现的变化有：（1）足突和滤过裂隙数量减少；（2）许多残余裂隙中出现封闭连接，同时裂隙隔膜移位；（3）基底膜致密中央部分（致密层）变薄，其与上皮之间的间隙（外侧稀疏层）相应增宽；（4）上皮细胞胞饮作用增强，蛋白吸收液滴或溶酶体数量增加。在冷冻断裂标本中，可见封闭连接范围有限，仅由几条链组成，表明它们不完整，代表封闭斑或束状带而非紧密连接。疾病后期（10至15天），裂隙数量或排列无进一步明显变化，但出现其他改变：（1）可见基底膜裸露区域，最初上皮与基底膜部分分离，最终完全分离；（2）大空泡或吞噬体数量增加，完全浓缩的溶酶体数量减少；（3）在部分分离的上皮与基底膜之间的间隙中可见基底膜样物质。本研究的新发现有：（1）明确了急性氨基核苷肾病中肾小球上皮早期（可逆）与晚期（可能不可逆）变化；（2）描绘了残余上皮裂隙的结构；（3）描述了上皮与基底膜之间连接逐渐松弛导致局灶性或完全上皮细胞脱离；（4）提供证据表明肾小球上皮溶酶体系统（在蛋白吸收和浓缩方面）在疾病后期出现耗竭。现有证据总结表明，肾小球主要滤过器肾小球基底膜在氨基核苷肾病中存在缺陷，导致蛋白渗漏增加。然而，氨基核苷的主要作用部位似乎在上皮，导致产生有缺陷的基底膜。
