Beneficial effects of integrin αvβ3-blocking RGD peptides in early but not late phase of experimental glomerulonephritis

Background. Integrin alpha v beta 3 plays an important role in the regulation of cell proliferation and neoangiogenesis. We found mesangial de novo expression of integrin alpha v beta 3 in mesangioproliferative glomerulonephritis (MesGN). The aim of the study was to clarify if blockade of alpha v beta 3 integrin with the specific alpha v beta 3-blocking cyclic peptide RGDdFV (cRGD) has beneficial effects on the course of this disease. Methods. Habu snake venom (Habu) GN was induced in male C57BL/6 mice 1 week after uninephrectomy (6 mg Habu toxin/kg body weight intravenously). After 24 h, nephritic animals received alpha v beta 3-inhibitory cRGD or cRAD control peptides for 3 or 7 days, respectively. The kidneys were investigated using morphometry, immunohistochemistry and TaqMan polymerase chain reaction. Results. At Day 3, serum creatinine and albuminuria were lower after cRGD compared to cRAD treatment. At Day 3, glomerulosclerosis index, percentage of glomerular injury, mesangial cell (MC) number and volume density of mesangial matrix were significantly lower (P < 0.05) in cRGD-treated mice than in cRAD-treated controls. At Day 7, only a mild effect of cRGD on mesangial matrix expansion and fibronectin messenger RNA was still detectable (P < 0.05). Complementary in vitro studies in MCs revealed that inhibition of alpha v beta 3 by cRGD-blocked adhesion, reduced proliferation and increased apoptosis of MCs. Conclusion. Habu GN inhibition of integrin alpha v beta 3 by cRGD partly ameliorates early injury but has no or only mild effects on late glomerular lesions.