Fasth A L, Hoyer J R, Seiler M W
Department of Pediatrics, UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance 90509.
Clin Immunol Immunopathol. 1988 Apr;47(1):47-61. doi: 10.1016/0090-1229(88)90144-4.
The effects of unilateral ureteral obstruction were studied in mice. Obstruction for 24 hr led to the formation of extratubular Tamm-Horsfall protein (TH) aggregates within the renal interstitium and at the base of distal convoluted tubular (DCT) cells. These DCT deposits were shown by ultrastructural analysis to be entirely extracellular. They had the fibrillar substructure characteristic of TH and had not been seen after urinary obstruction in other species. As a consequence of retrograde flow of urine to glomeruli, obstruction also caused TH aggregates to form within Bowman's spaces. These glomerular casts of TH were detected throughout the 3-week period of study after the release of unilateral obstruction. High serum titers of IgG antibodies to TH developed in mice intradermally immunized with TH but were not observed after obstruction alone. Circulating anti-TH antibodies combined with TH present on the basal surfaces of the thick ascending limb of the loop of Henle cells and DCT cells to form immune complexes in situ. Interstitial inflammation in the areas surrounding subepithelial tubular immune deposits was not present in the kidneys of immunized mice and was not selectively induced by temporary obstruction. However, foci of inflammation were seen in all obstructed kidneys. At later times, inflammatory foci in previously obstructed kidneys were associated with progressive scarring, primarily in polar regions. The location and severity of these changes within kidneys produced by obstruction in immunized mice did not differ from those in unimmunized mice. The titers of anti-TH antibodies in immunized mice were not enhanced or depressed as a consequence of unilateral ureteral obstruction. These studies demonstrate that complete obstruction of urinary flow in the mouse for periods as short as 24 hr may lead to progressive segmental renal scarring. These studies further indicate that increasing the quantities of extracellular TH by obstruction does not facilitate inflammatory responses to TH immune complexes formed in situ. While exposure of renal tissue to highly toxic components of extravasated urine may play a crucial role in inflammatory responses, autoimmunity to TH was not implicated as a contributing factor by the present studies in mice.
在小鼠中研究了单侧输尿管梗阻的影响。梗阻24小时导致肾间质和远曲小管（DCT）细胞基部形成管外Tamm-Horsfall蛋白（TH）聚集体。超微结构分析显示，这些DCT沉积物完全位于细胞外。它们具有TH特有的纤维亚结构，在其他物种尿路梗阻后未见此现象。由于尿液逆行流入肾小球，梗阻还导致鲍曼间隙内形成TH聚集体。在单侧梗阻解除后的整个3周研究期间均检测到这些TH肾小球管型。用TH皮内免疫的小鼠产生了高血清滴度的抗TH IgG抗体，但仅梗阻后未观察到。循环抗TH抗体与Henle袢升支粗段细胞和DCT细胞基表面的TH结合，原位形成免疫复合物。免疫小鼠肾脏中上皮下肾小管免疫沉积物周围区域不存在间质炎症，临时梗阻也未选择性诱导间质炎症。然而，在所有梗阻的肾脏中均可见炎症灶。在后期，先前梗阻肾脏中的炎症灶与进行性瘢痕形成相关，主要在两极区域。免疫小鼠中梗阻引起的肾脏内这些变化的位置和严重程度与未免疫小鼠无异。单侧输尿管梗阻不会导致免疫小鼠中抗TH抗体滴度升高或降低。这些研究表明，小鼠尿路仅梗阻24小时就可能导致进行性节段性肾瘢痕形成。这些研究进一步表明，通过梗阻增加细胞外TH的量并不能促进对原位形成的TH免疫复合物的炎症反应。虽然肾组织暴露于外渗尿液的高毒性成分可能在炎症反应中起关键作用，但本研究在小鼠中未发现对TH的自身免疫是一个促成因素。
