The proposed research is based on the hypothesis that autacoids such as platelet activating factor and eicosanoids are important mediators and modulators of glomerular immune injury. We believe that the autocrine and paracrine actions of these autacoids alters glomerular mesangial function both in vitro ad in vivo and, hence, plays an important role int he development of glomerular immune injury. We will evaluate the roles of platelet activating factor and eicosanoids (leukotrienes, thromboxane and prostaglandins) in three models of experimental glomerular disease. These models are: nephrotoxic serum nephritis, immune complex nephropathy induced by cationic bovine gamma globulin, and murine systemic lupus erythematosus. In these models, we will assess glomerular synthesis of platelet activating factor and eicosanoids, and we will evaluate the therapeutic benefits of the following drugs: platelet activating factor receptor blockage; leukotriene D4 receptor blockage; inhibitor of leukotriene B4 and leukotriene C4 synthesis; inhibitors of thromboxane synthesis and thromboxane receptors. these agents will be administered both acutely and chronically and the beneficial effects assessed through measurements of glomerular function, glomerular morphology and glomerular synthesis of these autacoids. Additionally, we will monitor the in vivo expression of genes controlling the synthesis of fibronectin and collagen. Glomerular mesangial cell cultures from rats and humans will be used in vitro to study the effects of immune stimulation on mesangial synthesis of platelet activating factor, eicosanoids, and matrix proteins including fibronectin and collagens. Immune stimulation will be induced with immune complexes, membrane attack complex, and leukocytes. These experiments will enhance our understanding of mesangial function and biochemistry under conditions which mimic immunologic injury in vivo. We wish to pursue in depth, the effects of platelet activating factor on cultured mesangial cells. These experiments will quantitate and characterize platelet activating factor receptors, G protein linkage of receptors and phospholipases, and intracellular events of signal transduction including phospholipase A2 and phospholipase C-mediated changes. Furthermore, we will test the hypothesis that both positive and negative feedback actions exist mediated through protein kinase C and cyclic AMP-protein kinase A.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041684-02
Application #
3242521
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Alexanian, Anna; Miller, Bradley; Roman, Richard J et al. (2012) 20-HETE-producing enzymes are up-regulated in human cancers. Cancer Genomics Proteomics 9:163-9
Sorokin, Andrey (2011) Endothelin signaling and actions in the renal mesangium. Contrib Nephrol 172:50-62
Yang, Chen; Sorokin, Andrey (2011) Upregulation of fibronectin expression by COX-2 is mediated by interaction with ELMO1. Cell Signal 23:99-104
Pavlov, Tengis S; Chahdi, Ahmed; Ilatovskaya, Daria V et al. (2010) Endothelin-1 inhibits the epithelial Na+ channel through betaPix/14-3-3/Nedd4-2. J Am Soc Nephrol 21:833-43
Rufanova, Victoriya A; Alexanian, Anna; Ostendorf, Tammo et al. (2010) Endothelin signaling via guanine exchange factor C3G in renal glomerular mesangial cells. Can J Physiol Pharmacol 88:808-16
Chahdi, Ahmed; Sorokin, Andrey (2010) The role of beta(1)Pix/caveolin-1 interaction in endothelin signaling through Galpha subunits. Biochem Biophys Res Commun 391:1330-5
Rufanova, Victoriya A; Alexanian, Anna; Wakatsuki, Tetsuro et al. (2009) Pyk2 mediates endothelin-1 signaling via p130Cas/BCAR3 cascade and regulates human glomerular mesangial cell adhesion and spreading. J Cell Physiol 219:45-56
Moriyama, Takahito; Sorokin, Andrey (2009) BK virus (BKV): infection, propagation, quantitation, purification, labeling, and analysis of cell entry. Curr Protoc Cell Biol Chapter 26:Unit 26.2
Alexanian, Anna; Rufanova, Victoriya A; Miller, Bradley et al. (2009) Down-regulation of 20-HETE synthesis and signaling inhibits renal adenocarcinoma cell proliferation and tumor growth. Anticancer Res 29:3819-24
Rufanova, Victoriya A; Lianos, Elias; Alexanian, Anna et al. (2009) C3G overexpression in glomerular epithelial cells during anti-GBM-induced glomerulonephritis. Kidney Int 75:31-40

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