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* The Department of Medicine, SFVAMC/University of California, San Francisco; and
the Department of Pathology, University of California, San Francisco, USA
1Correspondence: 111J Medical Service, SFVAMC, 4150 Clement St., San Francisco, CA 94121, USA. E-mail: david.lovett{at}med.va.gov
ABSTRACT
Chronic kidney disease (CKD) and failure are problems of increasing importance. Regardless of the primary etiology, CKD is characterized by tubular atrophy, interstitial fibrosis, and glomerulosclerosis. It has been assumed that diminished matrix metalloproteinase (MMP) activity is responsible for the accumulation of the extracellular matrix (ECM) proteins and collagens that typify the fibrotic kidney. Here we demonstrate that transgenic renal proximal tubular epithelial expression of a specific enzyme, MMP-2, is sufficient to generate the entire spectrum of pathological and functional changes characteristic of human CKD. At the earliest point, MMP-2 leads to structural alterations in the tubular basement membrane, a process that triggers tubular epithelial-mesenchymal transition, with resultant tubular atrophy, fibrosis and renal failure. Inhibition of MMP-2, specifically in the early, prefibrotic stages of disease may offer an additional approach for treatment of these disabling disorders.—Cheng, S., Pollock, A. S., Mahimkar, R., Olson, J. L., Lovett, D. H. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury.
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