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      Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney Disease

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          Abstract

          Background

          Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving α3(IV), α4(IV), or α5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.

          Methods and Findings

          We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in α3(IV) −/− mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the α3(IV) −/− mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of α3(IV) −/− mice.

          Conclusions

          These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in α3(IV) −/− mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria.

          Abstract

          In a mouse model of Alport disease, matrix metalloproteinases appear to have a crucial dual role in disease progression, with an early pathogenic function and a later protective action.

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          Most cited references46

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          Basement membranes: structure, assembly and role in tumour angiogenesis.

          In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.
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            BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

            Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.
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              Pathophysiology of progressive nephropathies.

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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                April 2006
                7 March 2006
                : 3
                : 4
                : e100
                Affiliations
                [1] 1Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
                [2] 2Gene Expression Laboratory, Boys Town National Research Hospital, Omaha, Nebraska, United States of America
                [3] 3Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
                [4] 4Department of Surgery, University of Kansas School of Medicine, Wichita, Kansas, United States of America
                [5] 5Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America
                [6] 6Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts, United States of America
                [7] 7Division of Nephrology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                University of Edinburgh United Kingdom
                Author notes
                * To whom correspondence should be addressed. E-mail: rkalluri@ 123456bidmc.harvard.edu

                Author contributions. MZ, ZW, and RK designed the study. MZ and RK analyzed the data. MZ, MK, VHR, DC, JPR, and MCW collected data or carried out experiments for the study. CFS enrolled patients. MZ, VHR, DC, ZW, and RK contributed to writing the paper. DC participated in the electron microscopy studies and in situ zymography. JPR generated and provided the MMP-2 and MMP-9 double-knock-out mice used in this study and designed the conditions for their phenotypic and genotypic characterization. MCW conducted the experiments using Col4A3-deficient mice. ZW helped design the study and assisted with ZW's postdoctorate. J-PR assisted with cross-referencing. CFS provided nephrectomy specimens from patients with Alport syndrome and specimens from pre-renal-failure patients to help confirm portions of the theories.

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                10.1371/journal.pmed.0030100
                1391977
                16509766
                1d81eca7-a4a2-4ac4-b505-e0cc9ba45820
                Copyright: © 2006 Zeisberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 26 April 2005
                : 28 December 2005
                Categories
                Research Article
                Molecular Biology/Structural Biology
                Nephrology
                Renal Medicine

                Medicine
                Medicine

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