Beneficial effects of integrin αvß3-blocking RGD peptides in early but not late phase of experimental glomerulonephritis.

ABSTRACT

BACKGROUND: Integrin αvß3 plays an important role in the regulation of cell proliferation and neoangiogenesis. We found mesangial de novo expression of integrin αvß3 in mesangioproliferative glomerulonephritis (MesGN). The aim of the study was to clarify if blockade of αvß3 integrin with the specific αvß3-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 αvß3-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 αvß3 by cRGD-blocked adhesion, reduced proliferation and increased apoptosis of MCs. CONCLUSION: Habu GN inhibition of integrin αvß3 by cRGD partly ameliorates early injury but has no or only mild effects on late glomerular lesions.