Matrix metalloproteinases in kidney homeostasis and diseases

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases.

Fig. 1.

Domain structure of the matrix metalloproteinase (MMP) family. The MMPs are structurally composed of similar modular domains. The presence or absence of these domains, along with their substrate specificity, has been used to classify the MMPs into several subgroups. S, signal peptide; Pro, prodomain; Cat, catalytic domain; h, hinge region; F, furin sensitive cleavage site; Fn, fibronectin-like repeat; II, type II transmembrane domain; G, glycosylphosphatidylinositol (GPI)-anchor.

Fig. 2.

Crystal structure of MMP-1. Active human MMP-1 is shown as a ribbon diagram. The structure was determined with the help of a single amino acid mutation to create an inhibitor-free structure that should closely represent the active form. Four calcium ions and 2 zinc ions are part of the structure. Helices (hA, hB, hC) and strands (s1–5) are labeled, as are the 4 propeller-shaped blades of the hemopexin domain (bI–IV). Published with permission (54).

Fig. 3.

Expression profile of MMP/tissue inhibitors of metalloproteinases (TIMPs) along the nephron. The various MMPs and their inhibitors have unique expression profiles along the nephron. Currently known localizations are shown. An asterisk (*) denotes upregulation in renal pathological conditions, while a dagger (†) denotes downregulation in disease states. PCT, proximal convoluted tubule; LOH, loop of Henle; DCT, distal convoluted tubule; CD, collecting duct. Data are compiled from many original studies.

Fig. 4.

Roles of MMPs in renal inflammation. MMPs, together with TIMPs, regulate the activation, cytokine release, chemotaxis, proliferation, and apoptosis of multiple inflammatory cells.

Fig. 5.

Roles of MMPs in regulating epithelial-mesenchymal transition (EMT) and renal fibrosis. MMPs are instrumental in mediating tubular EMT via E-cadherin shedding and degradation of tubular basement membrane (TBM). MMPs, together with TIMPs, also regulate the proliferation/apoptosis of interstitial fibroblasts and glomerular mesangial cells. The proteolytic products of matrix by MMPs also play a role in regulating cellular activities such as endothelial cell growth and angiogenesis.