| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California, San Francisco; and the Northern California Institute for Research and Education, San Francisco, California
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-ß1 (TGF-ß1). 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-ß1 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-ß1. In addition, purified active gelatinase A alone is sufficient to induce epithelial-mesenchymal transformation in the absence of exogenous TGF-ß1. Gelatinase A may also mediate epithelial-mesenchymal transformation in a paracrine manner through the proteolytic generation of active TGF-ß1 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.
This article has been cited by other articles:
 |
|
 |
|
  C. A. Reichel, M. Rehberg, P. Bihari, C. M. Moser, S. Linder, A. Khandoga, and F. Krombach Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling J. Leukoc. Biol., April 1, 2008; 83(4): 864 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cao, C. Chiarelli, O. Richman, K. Zarrabi, P. Kozarekar, and S. Zucker Membrane Type 1 Matrix Metalloproteinase Induces Epithelial-to-Mesenchymal Transition in Prostate Cancer J. Biol. Chem., March 7, 2008; 283(10): 6232 - 6240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. F. Sanders, M. G. Huitema, R. Hanemaaijer, H. van Goor, C. G. M. Kallenberg, and C. A. Stegeman Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1927 - F1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Thrailkill, R. C. Bunn, C. S. Moreau, G. E. Cockrell, P. M. Simpson, H. N. Coleman, J. P. Frindik, S. F. Kemp, and J. L. Fowlkes Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes Diabetes Care, September 1, 2007; 30(9): 2321 - 2326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Willis and Z. Borok TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L525 - L534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Jansen, M. Kever, R. Rosch, E. Krott, M. Jansen, A. Alfonso-Jaume, S. Dooley, U. Klinge, D. H. Lovett, and P. R. Mertens Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts FASEB J, April 1, 2007; 21(4): 1047 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Daniel, K. Amann, B. Hohenstein, P. Bornstein, and C. Hugo Thrombospondin 2 Functions as an Endogenous Regulator of Angiogenesis and Inflammation in Experimental Glomerulonephritis in Mice J. Am. Soc. Nephrol., March 1, 2007; 18(3): 788 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Hewitson, I. Mookerjee, R. Masterson, C. Zhao, G. W. Tregear, G. J. Becker, and C. S. Samuel Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis Endocrinology, February 1, 2007; 148(2): 660 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. de Laplanche, K. Gouget, G. Cleris, F. Dragounoff, J. Demont, A. Morales, L. Bezin, C. Godinot, G. Perriere, D. Mouchiroud, et al. Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules Am J Physiol Renal Physiol, October 1, 2006; 291(4): F750 - F760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cheng, A. S. Pollock, R. Mahimkar, J. L. Olson, and D. H. Lovett Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury FASEB J, September 1, 2006; 20(11): 1898 - 1900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khandoga, J. S. Kessler, M. Hanschen, A. G. Khandoga, D. Burggraf, C. Reichel, G. F. Hamann, G. Enders, and F. Krombach Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver J. Leukoc. Biol., June 1, 2006; 79(6): 1295 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nasrallah and R. L. Hebert Prostacyclin signaling in the kidney: implications for health and disease Am J Physiol Renal Physiol, August 1, 2005; 289(2): F235 - F246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yamate, Y. Machida, M. Ide, M. Kuwamura, T. Kotani, O. Sawamoto, and J. LaMarre Cisplatin-Induced Renal Interstitial Fibrosis in Neonatal Rats, Developing as Solitary Nephron Unit Lesions Toxicol Pathol, February 1, 2005; 33(2): 207 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Margetts, P. Bonniaud, L. Liu, C. M. Hoff, C. J. Holmes, J. A. West-Mays, and M. M. Kelly Transient Overexpression of TGF-{beta}1 Induces Epithelial Mesenchymal Transition in the Rodent Peritoneum J. Am. Soc. Nephrol., February 1, 2005; 16(2): 425 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Masszi, L. Fan, L. Rosivall, C. A. McCulloch, O. D. Rotstein, I. Mucsi, and A. Kapus Integrity of Cell-Cell Contacts Is a Critical Regulator of TGF-{beta}1-Induced Epithelial-to-Myofibroblast Transition: Role for {beta}-Catenin Am. J. Pathol., December 1, 2004; 165(6): 1955 - 1967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stawowy, C. Margeta, H. Kallisch, N. G Seidah, M. Chretien, E. Fleck, and K. Graf Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-{beta}1 involves furin-convertase Cardiovasc Res, July 1, 2004; 63(1): 87 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Maric, K. Sandberg, and C. Hinojosa-Laborde Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17{beta}-Estradiol in the Aging Dahl Salt Sensitive Rat J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1546 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Robertson, S. Ali, B. J. McDonnell, A. D. Burt, and J. A. Kirby Chronic Renal Allograft Dysfunction: The Role of T Cell-Mediated Tubular Epithelial to Mesenchymal Cell Transition J. Am. Soc. Nephrol., February 1, 2004; 15(2): 390 - 397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu Epithelial to Mesenchymal Transition in Renal Fibrogenesis: Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention J. Am. Soc. Nephrol., January 1, 2004; 15(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gong, A. Rifai, E. M. Tolbert, J. N. Centracchio, and L. D. Dworkin Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3047 - 3060. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
