BERG, L. K.; DESAI, P.; AROPE, S.; KELLEY, K. M.; California State University, Long Beach: Insulin-like Growth Factor-binding Protein-2 (IGFBP-2) as a Possible Mediator for Angiotensin II (AngII) and Glucose-activated Kidney Mesangial Cells

Kidney glomerular mesangial cells exhibit activated proliferation and an over-production of extracellular matrix (ECM) in diabetic kidney cells or in response to experimental elevations in ambient glucose. These changes impair glomerular filtration and lead to eventual renal failure. Associated changes in the renal IGF axis have prompted the hypothesis that this axis plays a mediating role in the glomerulopathic processes, but the underlying mechanisms are not defined. The murine mesangial MES-13 cell line expresses IGFBP-2 exclusively of the other IGFBPs, providing an opportunity to study its putative role without interference from other IGFBPs. When cultured in diabetic glucose concentrations (>20 mM), the cells exhibit significantly activated production of several ECM components concomitant with a significant increase in IGFBP-2 levels. In addition, affinity crosslinking using ¹²⁵I-IGF-I indicates cell surface binding of endogenously-expressed IGFBP-2 is enhanced by the high ambient glucose. When IGF-I antibody is added, these glucose-induced changes are attenuated, suggesting that IGF-mediated events are involved. Furthermore, as AngII has recently been established as a factor mediating glucose-stimulated ECM expression, we have recently shown that it stimulates IGFBP-2 release in a dose-dependent manner. This effect is reduced by addition of the AT1 receptor antagonist, saralasin, while saralasin addition alone also reduces IGFBP-2 levels. In conclusion, data thus far indicate that AngII increases production of IGFBP-2 and ECM in MES-13 cells and suggest that IGF-I and/or IGFBP-2 may play a mediating role in glucose- and/or AngII-activated MES-13 cells. [Support by NIH grant #GM-50089 & NSF grant #IBN-9600783]