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

Abstract

BackgroundGlomerular 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 FindingsWe 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. ConclusionsThese 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.

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

“…Furthermore, MMPs including MMP-9 has been shown to exhibit an opposing role at different stages of disease progression including renal disease. [26][27][28] Overall, the above observations highlight the complex biological function of MMP-9 that has previously been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 in UUO model via MMP-9 inhibition.…”

Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome

“…It has long been suspected that proteolytic degradation of the GBM in Alport syndrome might underlie the progressive irregular GBM damage and podocyte foot process effacement. Type IV collagen from Alport kidneys is more susceptible to proteolytic degradation in vitro than type IV collagen from healthy kidneys, 12,40 presumably owing to the reduced number of interchain disulfide cross-links. 13 Recombinant MMP-12 will digest native type IV collagen, suggesting the collagen network is a suitable substrate for degradation.…”

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

“…Preservation of the glomerular basement membrane and the integrity of the extracellular matrix by inhibiting MMP-2 and MMP-9 before the onset of proteinuria (high amount of protein in urine) leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition in later stages of Alport disease causes accelerated glomerular and interstitial fibrosis. In addition, the expression patterns of MMP-2, MMP-3 and MMP-9 in the kidney glomerulus, seem to be linked in a compensatory manner, as was shown in genetic knock-out mouse models [46]. Similarly, differential actions and expression profiles of MMP-2 and MMP-9 have been implicated in platelet aggregation [48] as well as in the response to injury in the carotid artery [49].…”

“…Differential upregulation of MMP-2 and MMP-9 may have both pathogenic and protective effects during the development and progression of Alport syndrome [46], a progressive hereditary kidney disease (which leads to glomeruli damage and kidney failure) [47]. Preservation of the glomerular basement membrane and the integrity of the extracellular matrix by inhibiting MMP-2 and MMP-9 before the onset of proteinuria (high amount of protein in urine) leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition in later stages of Alport disease causes accelerated glomerular and interstitial fibrosis.…”