Glomerular protein levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 are lower in diabetic subjects.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate extracellular matrix turnover throughout the body, including in renal glomeruli. We investigated protein levels of multiple MMPs (MMP-1, MMP-2, MMP-3, and MMP-9) and TIMP-1 in glomeruli and investigated whether disease phenotypes were associated with levels of these proteins. Renal cortex was collected from 100 adult autopsy subjects arrayed across 17 tissue microarrays. Immunohistochemical staining intensity for each MMP and TIMP-1 was determined using quantitative color deconvolution techniques. We observed significantly decreased glomerular MMP-1 and TIMP-1 staining in subjects with diabetes, hypertension, and an estimated glomerular filtration rate <30 ml/min/1.73 m(2) in univariate analyses. MMP-1 staining, but not TIMP-1 staining, was inversely correlated with increased glomerular fibrosis (r = -0.40). In multivariable analysis, diabetes was robustly associated with decreased staining intensity. This study indicates that in human subjects, the long-term sequelae of diseases such as diabetes that cause chronic renal failure result in decreased TIMP-1 and MMP-1 proteins in renal glomeruli. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
Cornish
Toby C
TC
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Bagnasco
Serena M
SM
Macgregor
Anne M
AM
Lu
Jie
J
Selvin
Elizabeth
E
Halushka
Marc K
MK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000906:Antibodies / Q000276:immunology; D003116:Color; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005355:Fibrosis / Q000150:complications; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000150:complications; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D013194:Staining and Labeling; D046888:Tissue Array Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
D000906:Antibodies; D019715:Tissue Inhibitor of Metalloproteinase-1; D020781:Matrix Metalloproteinase 1