IGF-1 decreases collagen degradation in diabetic NOD mesangial cells - Implications for diabetic nephropathy

Nonobese diabetic (NOD) mice develop glomerulosclerosis shortly after the o nset of diabetes. We showed that mesangial cells (MCs) from diabetic mice e xhibited a stable phenotypic switch, consisting of both increased IGF-1 syn thesis and proliferation (Elliot SJ, Striker LJ, Hattori M, Yang CW, He CJ, Peten EP, Striker GE: Mesangial cells from diabetic NOD mice constitutivel y secrete increased amounts of insulin-like growth factor-I. Endocrinology 133:1783-1788, 1993). Because the extracellular matrix (ECM) accumulation i n diabetic glomerulosclerosis may be partly due to decreased degradation, w e examined the effect of excess IGF-1 on collagen turnover and the activity of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (T IMPs) in diabetic and nondiabetic NOD-MG. Total collagen degradation was re duced by 58 +/- 18% in diabetic NOD-MCs, which correlated with a. constitut ive decrease in MMP-2 activity and mRNA levels, and nearly undetectable MMP -9 activity and mRNA. TIMP levels were slightly decreased in diabetic NOD-M G. The addition of recombinant IGF-1 to nondiabetic NOD-MG resulted in a de crease in MMP-2 and TIMP activity. Furthermore, treatment of diabetic NOD-M C with a neutralizing antibody against IGF-1 increased the latent form, and restored the active form, of MMP-2, In conclusion, the excessive productio n of IGF-1 contributes to the altered ECM turnover in diabetic NOD-MG, larg ely through a reduction of MMP-2 activity, These data suggest that IGF-1 co uld be a major contributor to the development of diabetic glomerulosclerosi s.