In autosomal dominant polycystic kidney disease (ADPKD), the inexorable growth of numerous fluid-filled cysts leads to massively enlarged kidneys, renal interstitial damage, inflammation, and fibrosis, and progressive decline in kidney function. It has long been recognized that interstitial fibrosis is the most important manifestation associated with end-stage renal disease; however, the role of abnormal extracellular matrix (ECM) production on ADPKD pathogenesis is not fully understood. Early evidence showed that cysts in end-stage human ADPKD kidneys had thickened and extensively laminated cellular basement membranes, and abnormal regulation of gene expression of several basement membrane components, including collagens, laminins, and proteoglycans by cyst epithelial cells. These basement membrane changes were also observed in dilated tubules and small cysts of early ADPKD kidneys, indicating that ECM alterations were early features of cyst development. Renal cystic cells were also found to overexpress several integrins and their ligands, including ECM structural components and soluble matricellular proteins. ECM ligands binding to integrins stimulate focal adhesion formation and can promote cell attachment and migration. Abnormal expression of laminin-332 (laminin-5) and its receptor α6β4 stimulated cyst epithelial cell proliferation; and mice that lacked laminin α5, a component of laminin-511 normally expressed by renal tubules, had an overexpression of laminin-332 that was associated with renal cyst formation. Periostin, a matricellular protein that binds αVβ3- and αVβ5-integrins, was found to be highly overexpressed in the kidneys of ADPKD and autosomal recessive PKD patients, and several rodent models of PKD. αVβ3-integrin is also overexpressed by cystic epithelial cells, and the binding of periostin to αVβ3-integrin activates the integrin-linked kinase and downstream signal transduction pathways involved in tissue repair promoting cyst growth, ECM synthesis, and tissue fibrosis. This chapter reviews the roles of the ECM, integrins, and focal adhesion signaling in cyst growth and fibrosis in PKD.

中文翻译：

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多囊肾病中的细胞外基质、整合素和粘着斑信号传导。

在常染色体显性多囊肾病 (ADPKD) 中，大量充满液体的囊肿的不可阻挡的生长导致肾脏大量增大、肾间质损伤、炎症和纤维化，以及肾功能进行性下降。人们早就认识到间质纤维化是与终末期肾病相关的最重要的表现；然而，异常细胞外基质 (ECM) 产生对 ADPKD 发病机制的作用尚不完全清楚。早期证据表明，终末期人类 ADPKD 肾脏中的囊肿具有增厚和广泛层叠的细胞基底膜，并且囊肿上皮细胞对几种基底膜成分（包括胶原蛋白、层粘连蛋白和蛋白聚糖）的基因表达进行了异常调节。在早期 ADPKD 肾脏的扩张小管和小囊肿中也观察到这些基底膜变化，表明 ECM 改变是囊肿发展的早期特征。还发现肾囊性细胞过度表达几种整联蛋白及其配体，包括 ECM 结构成分和可溶性基质细胞蛋白。与整联蛋白结合的 ECM 配体刺激粘着斑形成，并可以促进细胞附着和迁移。laminin-332（laminin-5）及其受体α6β4的异常表达刺激囊肿上皮细胞增殖；缺乏层粘连蛋白 α5（通常由肾小管表达的层粘连蛋白 511 的组成部分）的小鼠会过度表达与肾囊肿形成相关的层粘连蛋白 332。Periostin，一种结合αVβ3-和αVβ5-整联蛋白的基质细胞蛋白，发现在 ADPKD 和常染色体隐性遗传 PKD 患者的肾脏以及几种 PKD 啮齿动物模型中高度过表达。αVβ3-整联蛋白也被囊性上皮细胞过度表达，骨膜蛋白与 αVβ3-整联蛋白的结合激活了整联蛋白相关激酶和下游信号转导通路，参与组织修复，促进囊肿生长、ECM 合成和组织纤维化。本章回顾了 ECM、整合素和粘着斑信号在 PKD 囊肿生长和纤维化中的作用。骨膜蛋白与 αVβ3-整联蛋白的结合激活了整联蛋白相关激酶和参与组织修复的下游信号转导通路，促进了囊肿生长、ECM 合成和组织纤维化。本章回顾了 ECM、整合素和粘着斑信号在 PKD 囊肿生长和纤维化中的作用。骨膜蛋白与 αVβ3-整联蛋白的结合激活了整联蛋白相关激酶和参与组织修复的下游信号转导通路，促进了囊肿生长、ECM 合成和组织纤维化。本章回顾了 ECM、整合素和粘着斑信号在 PKD 囊肿生长和纤维化中的作用。