Gelatinase A (MMP-2) Is Necessary and Sufficient for Renal Tubular Cell Epithelial-Mesenchymal Transformation

Abstract

Progressive renal interstitial fibrosis and tubular atrophy represent the final injury pathway for all commonly encountered forms of renal disease that lead to end-stage renal failure. It has been recently recognized that myofibroblastic cells are the major contributors to the deposition of interstitial collagens. While there are several potential cellular sources of myofibroblasts, attention has focused on the transformation of the organized tubular epithelium to the myofibroblastic phenotype, a process potently driven both in vitro and in vivo by transforming growth factor-beta1 (TGF-beta1). Integrity of the underlying basal lamina provides cellular signals that maintain the epithelial phenotype, and disruption by discrete proteases could potentially initiate the transformation process. We demonstrate that TGF-beta1 coordinately stimulates the synthesis of a specific matrix metalloproteinase, gelatinase A (MMP-2), and its activator protease, MT1-MMP (MMP-14), and that active gelatinase A is absolutely required for epithelial-mesenchymal transformation induced by TGF-beta1. In addition, purified active gelatinase A alone is sufficient to induce epithelial-mesenchymal transformation in the absence of exogenous TGF-beta1. Gelatinase A may also mediate epithelial-mesenchymal transformation in a paracrine manner through the proteolytic generation of active TGF-beta1 peptide. MT1-MMP and gelatinase A were co-localized to sites of active epithelial-mesenchymal transformation and basal lamina disruption in the rat remnant kidney model of progressive renal fibrosis. These studies indicate that a discrete matrix metalloproteinase, gelatinase A, is capable of inducing the complex genetic rearrangements that characterize renal tubular epithelial-mesenchymal transformation.

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

“…Glomerulosclerosis and tubulointerstitial fibrosis in 4M and 12M DSS rats aging (17,23,37). Recent studies have shown that in addition to excessive synthesis of the ECM, the presence of amorphous ECM deposits in progressive renal disease are due to decreased activity of the ECM degradative pathway (38,39). Our studies extend these findings by providing evidence of decreased activity of MMP, specifically MMP-9 and MMP-2, in the 12M kidney, thus contributing to the age-related accumulation of ECM in tubulointerstitial fibrosis and glomerulosclerosis.…”

Gelatinase-mediated migration and invasion of cancer cells

“…The CTT peptide has also been used to modify the natural tropism of adenovirus for a therapeutic gene delivery in a rabbit restenosis model (Turunen et al, 2002). In addition, CTT peptide has been used to localize gelatinase activity in tissue samples using in situ zymography (Pirilä et al, 2001), and to evaluate the contribution of gelatinases in various biological processes including vasoconstriction, epithelial-mesenchymal transition and hepatitis (Cheng and Lovett, 2003;Fernandez-Patron et al, 2000;Franzke et al, 2002).…”

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…The role of MMPs as EMT inducers has been described in kidney, lung, ovary, oral, and mammary epithelium [52][53][54][55][56][57]. Their mechanism of action involves the processing and activation of pro-TGF-β in the ECM, as well as the direct proteolysis of E-cadherin [53,55,57].…”