BERG, LK; DESAI, P; AROPE, SA; KELLEY, KM: Insulin-like Growth Factor-binding Protein-2 (IGFBP-2) and Angiotensin II (AngII) in Glucose-activated Murine Kidney Mesangial Cells

With high ambient glucose (e.g., in diabetes), glomerular mesangial cells show activated proliferation and an over-production/accumulation of extracellular matrix (ECM). These changes lead to impaired glomerular filtration and renal failure. Associated changes in the renal IGF axis have prompted the hypothesis that this axis plays a direct role in initiating the glomerulopathic processes, but this has not been well established nor are the underlying mechanisms defined. The murine mesangial (MES-13) cell 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 activated production of several ECM components concomitant with a substantial increase in IGFBP-2 levels and an enhanced sensitivity to stimulation by added IGF-I. When ¹²⁵I-IGFBP-2 is added exogenously to cells, it distributes predominantly (>95%) to the membranes. In addition, affinity crosslinking using ¹²⁵I-IGF-I indicates cell surface binding of endogenous IGFBP-2 and, interestingly, this binding is increased in high ambient glucose. AngII, recently been established as a factor mediating glucose-stimulated ECM expression, significantly stimulates IGFBP-2 release in a dose-dependent manner. This effect is blocked by addition of the AT1 receptor antagonist, saralasin, which alone can also reduce IGFBP-2 levels. The data thus far indicate that AngII upregulates IGFBP-2 levels in MES-13 cells and suggest that the 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]