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.