Viquez Olga M, Yazlovitskaya Eugenia M, Tu Tianxiang, Mernaugh Glenda, Secades Pablo, McKee Karen K, Georges-Labouesse Elizabeth, De Arcangelis Adele, Quaranta Vito, Yurchenco Peter, Gewin Leslie C, Sonnenberg Arnoud, Pozzi Ambra, Zent Roy
Division of Nephrology and Hypertension and Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
Matrix Biol. 2017 Jan;57-58:244-257. doi: 10.1016/j.matbio.2016.12.003. Epub 2016 Dec 30.
Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound α and β subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system is poorly defined. Integrin α3β1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of α6 containing integrins (α6β1 and α6β4), the other major laminin receptors, is unknown. Patients with mutations in α6 containing integrins not only develop epidermolysis bullosa, but also have abnormalities in the kidney collecting system. In this study, we show that selectively deleting the α6 or β4 integrin subunits at the initiation of ureteric bud development in mice does not affect morphogenesis. However, the collecting system becomes dilated and dysmorphic as the mice age. The collecting system in both null genotypes was also highly susceptible to unilateral ureteric obstruction injury with evidence of excessive tubule dilatation and epithelial cell apoptosis. Mechanistically, integrin α6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that α6 integrins are important for maintaining the integrity of the kidney collecting system by enhancing tight adhesion of the epithelial cells to the basement membrane. These data give a mechanistic explanation for the association between kidney collecting system abnormalities in patients and epidermolysis bullosa.
层粘连蛋白是肾集合系统基底膜的主要成分。整合素是由非共价结合的α和β亚基形成的跨膜受体，作为层粘连蛋白受体，但其在肾集合系统发育和稳态中的作用尚不明确。整合素α3β1是主要的层粘连蛋白受体之一，在肾集合系统发育中起次要作用，而另一种主要的层粘连蛋白受体——含α6的整合素（α6β1和α6β4）的作用尚不清楚。含α6的整合素发生突变的患者不仅会患大疱性表皮松解症，肾集合系统也会出现异常。在本研究中，我们发现，在小鼠输尿管芽发育开始时选择性缺失α6或β4整合素亚基并不影响形态发生。然而，随着小鼠年龄增长，集合系统会扩张并出现畸形。两种基因敲除小鼠的集合系统对单侧输尿管梗阻损伤也高度敏感，有肾小管过度扩张和上皮细胞凋亡的迹象。从机制上讲，整合素α6基因敲除的集合管细胞在黏附于层粘连蛋白时无法承受高机械力。因此，我们得出结论，α6整合素通过增强上皮细胞与基底膜的紧密黏附，对维持肾集合系统的完整性很重要。这些数据为患者肾集合系统异常与大疱性表皮松解症之间的关联提供了一个机制解释。
