alpha 8 Integrin in glomerular mesangial cells and in experimental glomerulonephritis

Background. Mesangial cell (MC) proliferation and extracellular matrix accu mulation are typical responses of renal glomeruli to injury. Extracellular matrix components are known to affect MC behavior, which is mediated primar ily via integrin receptors of the beta 1 family. In addition to alpha 1, al pha 3, alpha 5, and alpha 6 chains of beta 1 integrins, recent studies have shown the alpha 8 chain to be expressed in glomeruli and renal vasculature . alpha 8 beta 1 can serve as a receptor for fibronectin, which is abundant in the mesangium. We investigated the glomerular expression pattern of the alpha 8 chain in renal tissues of mouse, rat, and humans as well as in cul tured MCs. In addition, the regulation of alpha 8 expression in MCs was stu died in culture and in nephritic rats. Methods. The expression of alpha 8 protein in kidney tissue and cultured MC s was investigated by immunohistochemistry, immunocytochemistry, and Wester n blotting. The effects of TGF-beta 1 on alpha 8 mRNA levels in MCs were st udied by Northern blot analysis. In addition, time course studies of glomer ular abundance and localization of alpha 8 were performed in rats with mesa ngioproliferative anti-TThy1.1 nephritis. Results. In tissue sections of normal human, rat, and mouse kidney, we foun d strong immunohistochemical staining for alpha 8 in the mesangium and in t he media of renal arterioles. Double staining for ocs and Thy1.1, a surface antigen of rat MCs, showed alpha 8 to be specifically expressed in MCs but not in glomerular endothelial and epithelial cells. In anti-Thy1.1 nephrit is of rats, the glomerular abundance of alpha 8 protein was reduced in the early mesangiolytic phase but was increased greatly with subsequent MC prol iferation, peaking at day 6 of disease. At later stages of this reversible form of nephritis, the number of MCs and the extent mesangial alpha 8 stain ing declined to control levels. Cell culture experiments revealed that fres hly plated MCs organize alpha 8 into focal contacts within one hour after a ttachment to fibronectin and vitronectin substrata, showing colocalization with focal contact proteins vinculin and talin. Stimulation of MCs with tra nsforming growth factor-beta 1 led to increases of alpha 8 mRNA and protein levels. Conclusions. These results show that in human, rat, and mouse glomeruli, al pha 8 integrin is strongly and exclusively expressed in MCs. Gene expressio n of alpha 8 is regulated in cultured MCs, and alpha 8 protein abundance is regulated in vivo and in MC culture. It is currently unclear what function al properties this integrin receptor protein has with regard to MC anchorag e to extracellular matrix and modulation of the MC phenotype in normal and diseased glomeruli. However, in view of its abundance in the mesangium, alp ha 8 beta 1 integrin could be an important MC receptor of matrix ligands an d may play a role in the embryology, physiology, and pathophysiology of the glomerular capillary tuft.