Altered expression of transforming growth factor-βs in chronic renal rejection

We examined the altered expression of transforming growth factor-βs in chronic renal rejection in humans, including transforming growth factor beta-1 (TGF-β1), TGF-β2, TGF-β3 and their receptors, transforming growth factor beta receptor type I (TβR-I) and TβR-II. Using Northern blot analysis and immunohistochemistry, 10 specimens of chronically rejected and g normal kidney samples were analyzed. By Northern blot analysis the expression of mRNA encoding TGF-β1, TGF-β2, TGF-β3 (P < 0.02), TβR-I and TβR-II (P < 0.02) was decreased in chronically rejected renal cortex samples, compared to normal controls. Immunohistochemical analysis of the normal renal cortex showed strong immunostaining for TGF-β1 and TGF-β3, and mild immunostaining for TGF-β2 in the proximal and distal tubulointerstitium, but no signal for any of the TGF-β isoforms in the glomeruli or in the cortical vessels. In sharp contrast, the glomeruli and the cortical vessels of the rejected kidney specimens exhibited strong immunostaining for TGF-β1 and TGF-β3, whereas the tubules revealed a decrease in immunoreactivity. TβRI and TβRII immunostaining showed similar changes as observed with TGF-β1 and TGF-β3 antibodies. There was a concomitant increase in B-cell accumulation in the glomeruli, while T-cells and macrophages were diffusely abundant in the rejected samples. Since TGF- βs are potent inducers of extracellular matrix proteins and have been shown to be involved in fibrotic disease, the increase in TGF-β1 and TGF-β3 immunoreactivity in the glomeruli suggests that there is a redistribution in TGF-β expression in chronic renal allograft rejection. Together with changes affected by B-cell mediated immunity, the above alterations might contribute to the histopathological changes that occur in this disorder, such as intimal fibrosis, arteriosclerosis and glomerular and tubular sclerosis.