Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

Hyperglycemia stimulates secretion of alpha V beta 3 ligands from vascular cells, including endothelial cells, resulting in activation of the alpha V beta 3 integrin. This study determined whether blocking ligand occupancy of alpha V beta 3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab) 2 fragment of an antibody directed against the extracellular domain of the beta 3-subunit, and 10 received a control IgG F(ab)(2) for 18 weeks. Nondiabetic pigs excreted 115 +/- 50 mu g of protein/mg creatinine compared with control F(ab)(2)-treated diabetic animals (218 +/- 57 mu g/mg), whereas diabetic animals treated with the anti-beta 3 F(ab)(2) excreted 119 +/- 55 mu g/mg (P < .05). Mesangial volume/glomerular volume increased to 21 +/- 2.4% in control-treated diabetic animals compared with 14 +/- 2.8% (P < .01) in animals treated with active antibody. Diabetic animals treated with control F(ab)(2) had significantly less glomerular podocin staining compared with nondiabetic animals, and this decrease was attenuated by treatment with anti-beta 3 F(ab)(2). Glomerular basement membrane thickness was increased in the control, F(ab)(2)-treated diabetic animals (212 +/- 14 nm) compared with nondiabetic animals (170 +/- 8.8 nm), but it was unchanged (159.9 +/- 16.4 nm) in animals receiving anti-beta 3 F(ab)(2). Podocyte foot process width was greater in control, F(ab)(2)-treated, animals (502 +/- 34 nm) compared with animals treated with the anti-beta 3 F(ab)(2) (357 +/- 47 nm, P < .05). Renal mu 3 tyrosine phosphorylation decreased from 13 934 +/- 6437 to 6730 +/- 1524 (P < .01) scanning units in the anti-mu 3-treated group. We conclude that administration of an antibody that inhibits activation of the beta 3-subunit of alpha V beta 3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy, suggesting that it may have utility in preventing the progression of this disease complication.