Tubulointerstitial De Novo Expression of the α8 Integrin Chain in a Rodent Model of Renal Fibrosis - A Potential Target for Anti-Fibrotic Therapy?

In the normal kidney, the alpha 8 integrin chain is expressed only on mesangial cells and vascular smooth muscle cells. alpha 8 integrin ligates several matrix molecules including fibronectin, osteopontin and fibrillin-1. Recently, we detected de novo expression of alpha 8 integrin on epithelial cells in renal cysts. We hypothesized that the alpha 8 integrin chain is induced in tubular epithelia undergoing dedifferentiation and contributes to the fibrotic response in the tubulointerstitium (TI) after unilateral ureteral obstruction (UUO). After induction of UUO in rats by ligation of the right ureter, increased expression of the alpha 8 integrin chain and its ligands was observed. In the TI, alpha 8 integrin was localized to cytokeratin-positive epithelial cells and to interstitial fibroblasts; and colocalized with its ligands. In mice underexpressing alpha 8 integrin UUO led to collagen deposition and fibroblast activation comparable to wild types. Mice lacking alpha 8 integrin showed even more TI damage, fibroblast activation and collagen deposition after UUO compared to wild type mice. We conclude that the expression of the alpha 8 integrin chain and its ligands is strongly induced in the TI after UUO, but underexpression of alpha 8 integrin does not attenuate TI fibrosis. Mice lacking the alpha 8 integrin chain are even more susceptible to TI damage than wild type mice. Thus, interactions of alpha 8 integrin with its ligands do not seem to contribute to the development or progression of TI fibrosis in UUO. Targeting alpha 8 integrin might not be a useful approach for anti-fibrotic therapy.