Effects of anti-α1 integrin subunit antibody on anti-Thy-1 glomerulonephritis

Abstract

α1/β1 integrin is a potential collagen-binding extracellular matrix receptor that mediates collagen-dependent cell adhesion, proliferation, migration, and collagen matrix assembly and thereby may participate in the wound healing and pathologic scarring observed in some damaged organs. To clarify the role of α1β1 integrin predominantly expressed on the mesangial cell (MC) surface in nephritic glomeruli, we investigated the involvement of MC-α1/β1 integrin in rat anti-Thy-1 glomerulonephritis (GN) by administering function-blocking monoclonal mouse anti-rat al integrin subunit antibody (anti-al Ab). Assay of collagen types I and IV mixed gel contraction, an in vitro model of pathologic collagen matrix remodeling, with function-blocking anti-α1 Ab and anti-β1 Ab, revealed that collagen I and IV matrix reorganization is mediated by MC-α1β1 integrin. In addition, conditioned medium from isolated Day 3 anti-Thy-1 nephritic glomeruli showed increased activity of MC-α1β1 integrin-induced mixed collagen gel contraction as compared with that from isolated normal rat glomeruli. Treatment of Day 3 conditioned medium with anti-platelet-derived growth factor-BB antibody significantly inhibited conditioned media-induced gel contraction, whereas treatment with anti-transforming growth factor-β antibody did not have a significant effect. Rats that received anti-α1 Ab from the left renal artery 3 days after anti-Thy-1 GN induction showed significant decreases of glomerular hypercellularity and mesangial matrix accumulation, including collagen I and IV in the left kidney, compared with those rats in which the left kidney received control mouse IgG1. These results suggest that MC-α1β1 integrin is an important extracellular matrix receptor mediating mesangial remodeling characterized by MC proliferation and mesangial matrix reorganization in anti-Thy-1 GN. Platelet-derived growth factor-BB may be involved in early collagen matrix reorganization leading to pathologic mesangial remodeling in this GN model.