Kalluri R, Shield C F, Todd P, Hudson B G, Neilson E G
Penn Center for Molecular Studies of Kidney Diseases, Renal Electrolyte and Hypertension Division, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-6144, USA.
J Clin Invest. 1997 May 15;99(10):2470-8. doi: 10.1172/JCI119431.
Normal glomerular capillaries filter plasma through a basement membrane (GBM) rich in alpha3(IV), alpha4(IV), and alpha5(IV) chains of type IV collagen. We now show that these latter isoforms are absent biochemically from the glomeruli in patients with X-linked Alport syndrome (XAS). Their GBM instead retain a fetal distribution of alpha1(IV) and alpha2(IV) isoforms because they fail to developmentally switch their alpha-chain use. The anomalous persistence of these fetal isoforms of type IV collagen in the GBM in XAS also confers an unexpected increase in susceptibility to proteolytic attack by collagenases and cathepsins. The incorporation of cysteine-rich alpha3(IV), alpha4(IV), and alpha5(IV) chains into specialized basement membranes like the GBM may have normally evolved to protectively enhance their resistance to proteolytic degradation at the site of glomerular filtration. The relative absence of these potentially protective collagen IV isoforms in GBM from XAS may explain the progressive basement membrane splitting and increased damage as these kidneys deteriorate.
正常的肾小球毛细血管通过富含IV型胶原α3(IV)、α4(IV)和α5(IV)链的基底膜（肾小球基底膜，GBM）过滤血浆。我们现在发现，在X连锁遗传性肾炎（XAS）患者的肾小球中，这些后几种异构体在生化上并不存在。相反，他们的肾小球基底膜保留了α1(IV)和α2(IV)异构体的胎儿分布，因为它们在发育过程中未能转换α链的使用。XAS患者肾小球基底膜中这些IV型胶原胎儿异构体的异常持续存在，也导致其对胶原酶和组织蛋白酶的蛋白水解攻击的易感性意外增加。富含半胱氨酸的α3(IV)、α4(IV)和α5(IV)链掺入像肾小球基底膜这样的特殊基底膜中，可能在正常情况下已经进化，以保护性地增强它们在肾小球滤过部位对蛋白水解降解的抵抗力。XAS患者肾小球基底膜中这些潜在的保护性IV型胶原异构体的相对缺乏，可能解释了随着这些肾脏恶化，基底膜逐渐分裂和损伤增加的原因。
