Miner J H, Sanes J R
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Cell Biol. 1996 Dec;135(5):1403-13. doi: 10.1083/jcb.135.5.1403.
Collagen IV is a major structural component of all basal laminae (BLs). Six collagen IV alpha chains are present in mammals; alpha 1 and alpha 2(IV) are broadly expressed in embryos and adults, whereas alpha 3-6(IV) are restricted to a defined subset of BLs. In the glomerular BL of the kidney, the alpha 1 and alpha 2(IV) chains are replaced by the alpha 3-5(IV) chains as development proceeds. In humans, mutation of the collagen alpha 3, alpha 4, or alpha 5(IV) chain genes results in a delayed onset renal disease called Alport syndrome. We show here that mice lacking collagen alpha 3(IV) display a renal phenotype strikingly similar to Alport syndrome: decreased glomerular filtration (leading to uremia), compromised glomerular integrity (leading to proteinuria), structural changes in glomerular BL, and glomerulonephritis. Interestingly, numerous changes in the molecular composition of glomerular BL precede the onset of renal dysfunction; these include loss of collagens alpha 4 and alpha 5(IV), retention of collagen alpha 1/2(IV), appearance of fibronectin and collagen VI, and increased levels of perlecan. We suggest that these alterations contribute, along with loss of collagen IV isoforms per se, to renal pathology.
IV型胶原蛋白是所有基底膜（BLs）的主要结构成分。哺乳动物体内存在六条IV型胶原蛋白α链；α1和α2（IV）在胚胎和成年个体中广泛表达，而α3 - 6（IV）则局限于特定的基底膜亚群。在肾脏的肾小球基底膜中，随着发育进程，α1和α2（IV）链会被α3 - 5（IV）链取代。在人类中，IV型胶原蛋白α3、α4或α5链基因的突变会导致一种迟发性肾病，称为奥尔波特综合征。我们在此表明，缺乏α3（IV）型胶原蛋白的小鼠表现出与奥尔波特综合征极为相似的肾脏表型：肾小球滤过率降低（导致尿毒症）、肾小球完整性受损（导致蛋白尿）、肾小球基底膜结构改变以及肾小球肾炎。有趣的是，在肾功能障碍发作之前，肾小球基底膜的分子组成就出现了许多变化；这些变化包括α4和α5（IV）型胶原蛋白的丢失、α1/2（IV）型胶原蛋白的保留、纤连蛋白和VI型胶原蛋白的出现以及硫酸乙酰肝素蛋白聚糖水平的升高。我们认为，这些改变与IV型胶原蛋白异构体本身的缺失一起，促成了肾脏病理变化。
