Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury.
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
Sunfa
S
The Department of Medicine, SFVAMC/University of California, San Francisco 94121, USA.
Pollock
Allan S
AS
Mahimkar
Rajeev
R
Olson
Jean L
JL
Lovett
David H
DH
D000818:Animals; D001284:Atrophy; D001483:Base Sequence; D001485:Basement Membrane / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D018450:Disease Progression; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007674:Kidney Diseases / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D007684:Kidney Tubules / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014746:Vimentin / Q000235:genetics
D002135:Calcium-Binding Proteins; D024042:Collagen Type I; D050958:HSP47 Heat-Shock Proteins; D061965:Matrix Metalloproteinase Inhibitors; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D014746:Vimentin; D020778:Matrix Metalloproteinase 2