title: Urinary matrix metalloproteinase activities: biomarkers for plaque angiogenesis and nephropathy in diabetes.
abstract: 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.
authors.affiliation: Cardiology Division, Dept. of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Ian B
authors.initials: IB
authors.lastname: McKittrick
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Bogaert
authors.forename: Kristen
authors.initials: K
authors.lastname: Nadeau
authors.forename: Janet
authors.initials: J
authors.lastname: Snell-Bergeon
authors.forename: Amber
authors.initials: A
authors.lastname: Hull
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Wang
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.forename: Karen S
authors.initials: KS
authors.lastname: Moulton
mesh_terms: D000293:Adolescent; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002648:Child; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000652:urine; D003928:Diabetic Nephropathies / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D058226:Plaque, Atherosclerotic / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D015415:Biomarkers; D020782:Matrix Metalloproteinases