A glimpse of matrix metalloproteinases in diabetic nephropathy

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.

Fig. (1). Regulatory mechanism involving MMPs in the diabetic nephropathy

Schematic drawing depicting the conceivable regulatory mechanism(s) in MMPs/TIMPs regulation by high glucose and advanced glycation end products (AGEs). Hyperglycemia and AGEs may induce ROS and TGF-β as well kidney tissue hypoxia. The ROS, hypoxia and high glucose lead to the activation of NF-κB, AP-1 and HIF-1 and thereby transcription of some of the MMPs. Inside the cells, the AGEs and ROS can activate PKC, which in turn can modulate the expression of TGF-β. TGF-β stimulates synthesis of matrix glycoproteins and modulation of MMPs/TIMPS via transcriptional mechanisms. High glucose also can active ERK1/2MAPK signaling and miRNAs, leading to alter MMPs expression. In addition, the mechanical stretch, besides dysregulation of MMPs and TIMPs, lead to increased extracellular matrix synthesis and its accumulation and decreased degradation, the hallmark features of diabetic nephropathy. Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; ECM, extracellular matrix; AP-1, activator protein 1; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; TGF-β, transforming growth factor β; ERK1/2, extracellular-signal-regulated kinases1/2; MAPKs, mitogen-activated protein kinases.