Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.
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 alpha3(IV), alpha4(IV), or alpha5(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.


RESULTS
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 alpha3(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 alpha3(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 alpha3(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 alpha3(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.
Zeisberg
Michael
M
Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Khurana
Mona
M
Rao
Velidi H
VH
Cosgrove
Dominic
D
Rougier
Jean-Philippe
JP
Werner
Michelle C
MC
Shield
Charles F
CF
Werb
Zena
Z
Kalluri
Raghu
R
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D050533:Glomerular Basement Membrane / Q000473:pathology* / Q000502:physiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000503:physiopathology*; D011507:Proteinuria / Q000503:physiopathology; D013379:Substrate Specificity; D016019:Survival Analysis; D015854:Up-Regulation
D001324:Autoantigens; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9