Matrix metalloproteinases: Their potential role in the pathogenesis of diabetic nephropathy

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
Endocrine (Impact Factor: 3.88). 11/2008; 35(1):1-10. DOI: 10.1007/s12020-008-9114-6
Source: PubMed


Matrix metalloproteinases (MMPs), a family of proteinases including collagenases, gelatinases, stromelysins, matrilysins, and membrane-type MMPs, affect the breakdown and turnover of extracellular matrix (ECM). Moreover, they are major physiologic determinants of ECM degradation and turnover in the glomerulus. Renal hypertrophy and abnormal ECM deposition are hallmarks of diabetic nephropathy (DN), suggesting that altered MMP expression or activation contributes to renal injury in DN. Herein, we review and summarize recent information supporting a role for MMPs in the pathogenesis of DN. Specifically, studies describing dysregulated activity of MMPs and/or their tissue inhibitors in various experimental models of diabetes, including animal models of type 1 or type 2 diabetes, clinical investigations of human type 1 or type 2 diabetes, and kidney cell culture studies are reviewed.

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Available from: John Fowlkes, Dec 26, 2013
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    • "MMP-2 knockout mice show reduced regeneration of axons following spinal contusion injury and impaired functional recovery (Hsu et al., 2006) highlighting the importance of MMPs for successful regeneration. A number of studies have described an increase in systemic MMPs in diabetes (Jacqueminet et al., 2006) and altered expression of MMPs has been implicated in the pathophysiology of a number of secondary complications including nephropathy (Thrailkill et al., 2009) and poor wound healing (Liu et al., 2009). To date, there is little information about the expression or activity of MMPs and/or their role in the regenerative deficits associated with diabetic neuropathy. "
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    ABSTRACT: Minocycline is an inhibitor of matrix metalloproteinases (MMPs) and has been shown to have analgesic effects. Whilst increased expression of MMPs is associated with neuropathic pain, MMPs also play crucial roles in Wallerian degeneration and nerve regeneration. In this study we examined the expression of MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1/-2 in the sciatic nerve of control and streptozotocin-induced diabetic rats treated with either vehicle or minocycline by quantitative PCR and gelatin zymography. We assessed the effects of minocycline on nerve conduction velocity and intraepidermal nerve fibre (IENF) deficits in diabetic neuropathy and investigated the effects of minocycline or MMP-2 on neurite outgrowth from primary cultures of dissociated adult rat sensory neurons.
    Full-text · Article · Aug 2014 · Experimental Neurology
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    • "More than 28 metalloproteinases have been described to date, and they are classified into different subgroups (collagenases, matrilysin, and stromelysin) according to their structure and function [117]. Metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) are members of the gelatinase family and were demonstrated in animal models and in vitro systems as important mechanisms of fibrosis in progressive chronic kidney disease [115, 118]. MMP-2 is normally expressed in mesangial cells, and it shows increased expression in these cells, as well as in podocytes during inflammatory states [46]. "
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    ABSTRACT: Focal segmental glomerulosclerosis (FSGS) is a glomerulopathy associated with nephrotic syndrome and podocyte injury. FSGS occurs both in children and adults and it is considered the main idiopathic nephrotic syndrome nowadays. It is extremely difficult to establish a morphological diagnosis, since some biopsies lack a considerable quantifiable number of sclerotic glomeruli, given their focal aspect and the fact that FSGS occurs in less than half of the glomeruli. Therefore, many biological molecules have been evaluated as potential markers that would enhance the diagnosis of FSGS. Some of these molecules and receptors are associated with the pathogenesis of FSGS and have potential use in diagnosis.
    Full-text · Article · Feb 2014 · Disease markers
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    • "Changes mediated by MMP-2 can be either physiologic or pathophysiologic in context. For instance, MMP-2 and -9 have been implicated not only in development and repair, but also in pathologies of the tracheal gland [32], renal system [34,35], tumors [20,30,36], bone [37-39], and circulatory system [40,41], among others. In the current study, knocking down MMP-2 both impaired the localized degradation of gelatin and inhibited AF cells from remodeling the collagen matrix. "
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    ABSTRACT: Introduction Degeneration of the intervertebral disc (IVD) is characterized by marked degradation and restructuring of the annulus fibrosus (AF). Although several matrix metalloproteinases (MMPs) have been found to be more prevalent in degenerate discs, their coordination and function within the context of the disease process are still not well understood. In this study, we sought to determine whether MMP-2 is associated with degenerative changes in the AF and to identify the manner by which AF cells use MMP-2. Methods Two established animal models of disc degeneration, static compression and transannular needle puncture of rodent caudal discs, were examined for MMP-2 immunopositivity. With lentiviral transduction of an shRNA expression cassette, we screened and identified an effective shRNA sequence for generating stable RNA interference to silence MMP-2 expression in primary rat AF cells. Gelatin films were used to compare gelatinase activity and spatial patterns of degradation between transduced cells, and both noninfected and nonsense shRNA controls. The functional significance of MMP-2 was determined by assessing the ability for cells to remodel collagen gels. Results Both static compression and 18-g annular puncture of rodent caudal discs stimulated an increase in MMP-2 activity with concurrent lamellar disorganization in the AF, whereas 22-g and 26-g needle injuries did not. To investigate the functional role of MMP-2, we established lentivirus-mediated RNAi to induce stable knockdown of transcript levels by as much as 88%, and protein levels by as much as 95% over a 10-day period. Culturing transduced cells on gelatin films confirmed that MMP-2 is the primary functional gelatinase in AF cells, and that MMP-2 is used locally in regions immediately around AF cells. In collagen gels, transduced cells demonstrated an inability to remodel collagen matrices. Conclusions Our study indicates that increases in MMP-2 observed in human degenerate discs are mirrored in experimentally induced degenerative changes in rodent animal models. AF cells appear to use MMP-2 in a very directed fashion for local matrix degradation and collagen remodeling. This suggests that MMP-2 may have a functionally significant role in the etiology of degenerative disc disease and could be a potential therapeutic target.
    Full-text · Article · Apr 2013 · Arthritis research & therapy
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