MECHANISMS OF METALLOPROTEINASE EXPRESSION BY OXIDANT STRESS

Barnes-Jewish Hospital, Saint Louis MO

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Abstract

DESCRIPTION (Abstract of the project) Injury to the kidney by a variety of stimuli may be associated with an acute inflammatory self-limiting process or it may progress with a chronic inflammatory response leading to fibrosis, tubular and glomerular obsolescence and eventually severe impairment of renal function. Some of the mechanisms by which a persistent inflammatory response leads to fibrosis and progressive renal failure are not completely understood. Neutrophil activity seems to be associated with endothelial damage and is part of the inflammatory response coordinated by a network of inflammatory cytokines and chemokines that are clearly involved in part of this process. Some of the molecules include interleukin 1B, tumor necrosis factor a, and interleukin-6. In addition to these lymphokines and chemokines, there is the potential for the generation of reactive oxygen intermediates which are part of the processes involved in injury to the kidney. The major oxidant species which have been implicated in renal injury are superoxide, hydrogen peroxide, and the hydroperoxy radical. In addition it has become recently obvious that other oxidant species which may have some relevance to a progressive renal injury is the generation of peroxynitrite. We believe that the respiratory burst oxidase which is the major extra mitochondrial site for the generation of superoxide is an important feature of these inflammatory responses. Products of the respiratory burst oxidase are capable of signaling through a variety of signal transduction processes leading to the activation of a number of pro-inflammatory genes which may have significant influence on the outcome of a renal inflammatory process. This grant, therefore, proposes to assess the role of oxidant species in the activation of many of these signal transduction processes and assess the importance of a novel matrix metalloproteinase (MMP-13), which was initially identified and associated with breast cancers. We have shown that inflammatory cytokines are capable of inducing and dramatically upregulating this matrix metalloproteinase which may be important and relevant to the regulation of extracellular matrix proteins. This proposal seeks to examine some of these interactions and the regulatory features which may influence the activity of this matrix metalloproteinase and its inhibitors.