Hartner A, Schöcklmann H, Pröls F, Müller U, Sterzel R B
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, Germany.
Kidney Int. 1999 Oct;56(4):1468-80. doi: 10.1046/j.1523-1755.1999.00662.x.
Mesangial cell (MC) proliferation and extracellular matrix accumulation are typical responses of renal glomeruli to injury. Extracellular matrix components are known to affect MC behavior, which is mediated primarily via integrin receptors of the beta1 family. In addition to alpha1, alpha3, alpha5, and alpha6 chains of beta1 integrins, recent studies have shown the alpha8 chain to be expressed in glomeruli and renal vasculature. alpha8beta1 can serve as a receptor for fibronectin, which is abundant in the mesangium. We investigated the glomerular expression pattern of the alpha8 chain in renal tissues of mouse, rat, and humans as well as in cultured MCs. In addition, the regulation of alpha8 expression in MCs was studied in culture and in nephritic rats.
The expression of alpha8 protein in kidney tissue and cultured MCs was investigated by immunohistochemistry, immunocytochemistry, and Western blotting. The effects of TGF-beta1 on alpha8 mRNA levels in MCs were studied by Northern blot analysis. In addition, time course studies of glomerular abundance and localization of alpha8 were performed in rats with mesangioproliferative anti-Thy1.1 nephritis.
In tissue sections of normal human, rat, and mouse kidney, we found strong immunohistochemical staining for alpha8 in the mesangium and in the media of renal arterioles. Double staining for alpha8 and Thy1.1, a surface antigen of rat MCs, showed alpha8 to be specifically expressed in MCs but not in glomerular endothelial and epithelial cells. In anti-Thy1.1 nephritis of rats, the glomerular abundance of alpha8 protein was reduced in the early mesangiolytic phase but was increased greatly with subsequent MC proliferation, peaking at day 6 of disease. At later stages of this reversible form of nephritis, the number of MCs and the extent mesangial alpha8 staining declined to control levels. Cell culture experiments revealed that freshly plated MCs organize alpha8 into focal contacts within one hour after attachment to fibronectin and vitronectin substrata, showing colocalization with focal contact proteins vinculin and talin. Stimulation of MCs with transforming growth factor-beta1 led to increases of alpha8 mRNA and protein levels.
These results show that in human, rat, and mouse glomeruli, alpha8 integrin is strongly and exclusively expressed in MCs. Gene expression of alpha8 is regulated in cultured MCs, and alpha8 protein abundance is regulated in vivo and in MC culture. It is currently unclear what functional properties this integrin receptor protein has with regard to MC anchorage to extracellular matrix and modulation of the MC phenotype in normal and diseased glomeruli. However, in view of its abundance in the mesangium, alpha8beta1 integrin could be an important MC receptor of matrix ligands and may play a role in the embryology, physiology, and pathophysiology of the glomerular capillary tuft.
系膜细胞（MC）增殖和细胞外基质积聚是肾小球对损伤的典型反应。已知细胞外基质成分会影响MC行为，这主要通过β1家族的整合素受体介导。除了β1整合素的α1、α3、α5和α6链外，最近的研究表明α8链在肾小球和肾血管系统中表达。α8β1可作为纤连蛋白的受体，纤连蛋白在系膜中含量丰富。我们研究了α8链在小鼠、大鼠和人类肾组织以及培养的MC中的肾小球表达模式。此外，还在培养物和肾炎大鼠中研究了MC中α8表达的调节。
通过免疫组织化学、免疫细胞化学和蛋白质印迹法研究肾组织和培养的MC中α8蛋白的表达。通过Northern印迹分析研究转化生长因子-β1对MC中α8 mRNA水平的影响。此外，对系膜增生性抗Thy1.1肾炎大鼠进行了α8的肾小球丰度和定位的时间进程研究。
在正常人、大鼠和小鼠肾脏的组织切片中，我们发现系膜和肾小动脉中膜有强烈的α8免疫组织化学染色。α8和Thy1.1（大鼠MC的表面抗原）的双重染色显示α8特异性表达于MC中，而不是肾小球内皮细胞和上皮细胞。在大鼠抗Thy1.1肾炎中，α8蛋白的肾小球丰度在早期系膜溶解期降低，但随着随后的MC增殖而大幅增加，在疾病第6天达到峰值。在这种可逆性肾炎的后期，MC数量和系膜α8染色程度降至对照水平。细胞培养实验表明，新鲜接种的MC在附着于纤连蛋白和玻连蛋白基质后1小时内将α8组织成粘着斑，显示与粘着斑蛋白纽蛋白和踝蛋白共定位。用转化生长因子-β1刺激MC导致α8 mRNA和蛋白水平增加。
这些结果表明，在人、大鼠和小鼠肾小球中，α8整合素在MC中强烈且特异性表达。α8的基因表达在培养的MC中受到调节，α8蛋白丰度在体内和MC培养中受到调节。目前尚不清楚这种整合素受体蛋白在正常和患病肾小球中对于MC锚定到细胞外基质以及MC表型调节方面具有哪些功能特性。然而，鉴于其在系膜中的丰度，α8β1整合素可能是基质配体的重要MC受体，并且可能在肾小球毛细血管襻的胚胎学、生理学和病理生理学中发挥作用。
