The overall long-term objectives of this research are to elucidate mechanisms by which cell surface metalloproteinases and their secreted counterparts are regulated and interact, activate and degrade peptides and proteins at the cell surface and extracellularly, as well as to define the roles of these proteases in health and diseases such as kidney and urinary tract disease. The work has led to the discovery and characterization of meprins, complex and unique mammalian metalloproteinases abundantly expressed at the brush border membrane of kidney and intestinal epithelial cells, and in leukocytes under certain conditions. The hypothesis is that meprins have a protective role in host defense in urinary tract infections, but that the alpha/beta form is actively involved in the pathophysiology of acute renal injury. In the next period, the Specific Aims are to: (1) Determine whether meprin alpha/beta is damaging to specific proteins in kidney epithelial cells in response to hypoxia or ischemia-reperfusion. Immunohistochemical, immunoprecipitation, and proteomic techniques will be used with kidneys and proximal tubules from wild-type and meprin knockout mice to identify specific targets of meprin interaction and hydrolysis in brush border membrane, cytosol and extracellular compartments. (2) Determine whether leukocytic meprins affect movement and activity of these inflammatory cells to ischemic kidney and enhance damage. Bone marrow cells from wild-type and meprin knockout mice will be destroyed by radiation, and replaced by donor leukocytes from wild-type or meprin knockout mice carrying a green- fluorescent protein. The movement of the donor leukocytes to kidneys in the chimeric mice subjected to ischemia-reperfusion, and the injury caused by meprin positive and negative leukocytes will give insight into the damage caused by these cells. (3) Determine whether meprin alpha secreted from the kidney, or leukocytic meprins, affect the establishment and severity of urinary tract disease. Mice of different meprin genotypes will be infected with uropathic bacteria in the bladder, and the susceptibility to bladder and kidney infections will be determined. The roles of leukocytic and kidney meprins will be assessed using the chimeric mice. The activation of meprins at sites of infection, concentrations of active beta-defensins, and interactions of meprin isoforms with bacteria will be assessed to gain insights into mechanisms of protection. The availability of the meprin alpha and beta knockout mice are unique resources for these studies, and fundamental knowledge of these metalloproteinases will lead to new concepts, treatments, and interventions for kidney and urinary tract diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Mullins, Christopher V
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Pennsylvania State University
Schools of Medicine
United States
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Bylander, John E; Ahmed, Faihaa; Conley, Sabena M et al. (2017) Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes. J Diabetes Res 2017:9035038
Keiffer, Timothy R; Bond, Judith S (2014) Meprin metalloproteases inactivate interleukin 6. J Biol Chem 289:7580-8
Bao, Jialing; Yura, Renee E; Matters, Gail L et al. (2013) Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin. Am J Physiol Renal Physiol 305:F714-26
Jefferson, Tamara; Auf dem Keller, Ulrich; Bellac, Caroline et al. (2013) The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprinýýýý and ADAM10. Cell Mol Life Sci 70:309-33
Garcia-Caballero, Agustin; Ishmael, Susan S; Dang, Yan et al. (2011) Activation of the epithelial sodium channel by the metalloprotease meprin * subunit. Channels (Austin) 5:14-22
Banerjee, Sanjita; Jin, Ge; Bradley, S Gaylen et al. (2011) Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 300:G273-82
Ongeri, Elimelda Moige; Anyanwu, Odinaka; Reeves, W Brian et al. (2011) Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia-reperfusion. Am J Physiol Renal Physiol 301:F871-82
Jefferson, Tamara; ?auševi?, Mirsada; auf dem Keller, Ulrich et al. (2011) Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo. J Biol Chem 286:27741-50
Banerjee, S; Oneda, B; Yap, L M et al. (2009) MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol 2:220-31
Sun, Qi; Jin, Hong-Jian; Bond, Judith S (2009) Disruption of the meprin alpha and beta genes in mice alters homeostasis of monocytes and natural killer cells. Exp Hematol 37:346-56

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