Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury

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.

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

“…29,30 MMP-2 appears both necessary and sufficient to induce tubular EMT. 19,21 Similarly, a recent study using transgenic mice with targeted expression of active MMP-2 in the proximal tubular epithelial cells has demonstrated Figure 6 The expression of mesenchymal marker proteins, including S100A4 (a, f, k), vimentin (b, g, l), and a-smooth muscle actin (aSMA) (c, h, m), marker of collagen synthesis heat shock protein-47 (HSP-47), which is known as the collagen-specific molecular chaperone (d, i, n), and macrophage infiltration (F4/ 80) (e, j, o), at day 14 post-unilateral ureteral obstruction (UUO) in MMP-2 þ / þ mice (a-e: WT mice), MMP-2 À/À mice (f-j: MMP-2 KO mice), and MMP-2 þ / þ mice treated with minocycline (k-o: Minocycline) (a-o, Â 400). In MMP-2 þ / þ mice at day 14 post-UUO, the expression of S100A4, vimentin, aSMA, and HSP-47 was evident in damaged tubular epithelial cells and interstitial cells (arrowhead in panels a-d).…”

“…21 Therefore, in addition to the pathogenic role of MMP-2 activity in the migration of tubular epithelial cells with mesenchymal phenotype into the interstitium accompanied by the destruction of TBM, recent studies have also indicated that MMP-2 can trigger EMT, probably through the disruption of TBM integrity.…”

“…In the EMT sites during renal fibrogenesis, MMPs mediate disruption of the integrity of the tubular basement membrane (TBM), which in turn promotes tubular epithelial cell EMT, and progressive interstitial fibrosis. [19][20][21] Recent studies have demonstrated that MMPs, especially gelatinases (MMP-2 and MMP-9) have major roles in the EMT process, and are involved in the renal tubular cell EMT both in vivo and in vitro. Although specific therapies that inhibit the progression of chronic renal disease are currently not available, modulation of MMPs in the EMT seems a legitimate therapeutic target with the aim of inhibition of renal fibrogenesis.…”

Expression of MMP-2 and TIMP-1 in Renal Tissue of Patients with Chronic Active Antibody-mediated Renal Graft Rejection

“…MMP-2 with relative molecule weight 72,000, a kind of collagenase A, may degrade collagen IV [3]. The disorder of MMP-2 expression might induce changes in tubular basement membrane structure, thus resulting to renal tubular epithelial cell transdifferentiation with tubular atrophy, fibrosis and renal dysfunction [4]. MMP-2 participates in the degradation of ECM, however TIMP-1 regulates its activity.…”

The Extracellular Matrix in Digestive Cancer

“…Furthermore, mice doubly deficient in these enzymes still achieve normal embryonic BM transmigration events such as pancreatic islet cell formation, suggesting that MMP-2 and MMP-9 are not essential for cellular invasion and migration [23,59]. The roles of MMP-2 and MMP-9, as well as the other MMPs, within the cancer microenvironment are still being fully characterized [23,[60][61][62].…”