Key metalloproteinase-mediated pathways in the kidney

Abstract

Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as soluble or membrane-bound proteases. These enzymes inactivate or activate other soluble or membrane-expressed mediator molecules, which enables them to control developmental processes, tissue remodelling, inflammatory responses and proliferative signalling pathways. The dysregulation of MMPs and ADAMs has long been recognized in acute kidney injury and in chronic kidney disease, and genetic targeting of selected MMPs and ADAMs in different mouse models of kidney disease showed that they can have detrimental and protective roles. In particular, MMP-2, MMP-7, MMP-9, ADAM10 and ADAM17 have been shown to have a mainly profibrotic effect and might therefore represent therapeutic targets. Each of these proteases has been associated with a different profibrotic pathway that involves tissue remodelling, Wnt–β-catenin signalling, stem cell factor–c-kit signalling, IL-6 trans-signalling or epidermal growth factor receptor (EGFR) signalling. Broad-spectrum metalloproteinase inhibitors have been used to treat fibrotic kidney diseases experimentally but more targeted approaches have since been developed, including inhibitory antibodies, to avoid the toxic side effects initially observed with broad-spectrum inhibitors. These advances not only provide a solid foundation for additional preclinical studies but also encourage further translation into clinical research. Dysregulated expression of metalloproteinases is observed in many forms of kidney disease. Here, the authors focus on the roles of the matrix metalloproteinase and a disintegrin and metalloproteinase families of proteins, as well as their regulators, in kidney disease processes and explore the therapeutic potential of novel metalloproteinase inhibitors. Expression and activity of the metalloproteinases matrix metalloproteinase 2 (MMP-2), MMP-7, MMP-9, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 can be dysregulated in acute and in chronic kidney disease. Murine knockout models indicate that these metalloproteinases preferentially have a profibrotic role in the kidney, in association with Wnt–β-catenin, stem cell factor–c-kit, IL-6, epidermal growth factor receptor or Notch signalling. MMPs are endogenously regulated, not only at the transcriptional level but also by the activity of tissue inhibitors of metalloproteinases; ADAM10 and ADAM17 are further regulated by adapter molecules. Novel metalloproteinase inhibitors with increased selectivity and reduced toxicity, such as monoclonal antibodies, have become available and their therapeutic potential should be explored in preclinical studies. Expression and activity of the metalloproteinases matrix metalloproteinase 2 (MMP-2), MMP-7, MMP-9, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 can be dysregulated in acute and in chronic kidney disease. Murine knockout models indicate that these metalloproteinases preferentially have a profibrotic role in the kidney, in association with Wnt–β-catenin, stem cell factor–c-kit, IL-6, epidermal growth factor receptor or Notch signalling. MMPs are endogenously regulated, not only at the transcriptional level but also by the activity of tissue inhibitors of metalloproteinases; ADAM10 and ADAM17 are further regulated by adapter molecules. Novel metalloproteinase inhibitors with increased selectivity and reduced toxicity, such as monoclonal antibodies, have become available and their therapeutic potential should be explored in preclinical studies.