Urinary matrix metalloproteinase activities: biomarkers for plaque angiogenesis and nephropathy in diabetes

Diabetic complications of nephropathy and accelerated atherosclerosis are associated with vascular remodeling and dysregulated angiogenesis. Matrix metalloproteinases (MMP) modify extracellular matrix during vascular remodeling and are excreted in urine of patients with vascular malformation or tumor angiogenesis. We hypothesized that urinary MMP activities would be sensitive biomarkers for vascular remodeling in diabetic complications. Activities of MMP-2, MMP-9, and its complex with neutrophil gelatinase-associated lipocalin (NGAL/MMP-9) were measured by substrate gel zymography in urine from nondiabetic (ND) and type 1 diabetic (T1D) rodents that were susceptible to both T1D-induced plaque angiogenesis and nephropathy, or nephropathy alone. Additionally, these urine activities were measured in ND and T1D adolescents. Urinary MMP-9, MMP-2, and NGAL/MMP-9 activities were increased and more prevalent in T1D compared with ND controls. Urinary MMP-2 activity was detected in mice with T1D-induced plaque neovascularization. In nephropathy models, urinary NGAL/MMP-9 and MMP-9 activities appeared before onset of albuminuria, whereas MMP-2 was absent or delayed. Finally, urinary MMP activities were increased in adolescents with early stages of T1D. Urinary MMP activities may be sensitive, noninvasive, and clinically useful biomarkers for predicting vascular remodeling in diabetic renal and vascular complications.