Most types of human as well as experimental glomerulonephritis are characterized by leukocyte (neutrophil. monocyte/macrophage) infiltration with the release of inflammatory mediators such as oxidants and proteases from these cells responsible for much of the glomerular injury. The mechanism by which these leukocytes are recruited from the circulation and localize in the glomeruli is unknown and is the focus of this research proposal. We hypothesize that leukocyte adhesion molecules (integrins) and their corresponding ligands expressed on resident glomerular cells (endothelial and mesangial) are necessary not only for leukocyte localization in the glomerulus but also for leukocyte mediated injury to the resident glomerular cells. The proposed studies to address this hypothesis will be two-fold in nature. We will use the classic model of anti-GBM nephritis in the rat to look at the role of adhesion molecules in vivo. This model is well characterized with a neutrophil dependent heterologous phase and a later macrophage dependent autologous phase. In both phases we will look for the upregulation of ELAM-1, VCAM-1, and ICAM-1 in the glomeruli and how this correlates with leukocyte infiltration. We will determine directly the importance of these adhesion molecules in this model by using specific monoclonal antibodies to ELAM-1, VCAM-1, and ICAM-1 as well as the leukocyte integrins CD18 and CD11b with our preliminary studies showing a protective effect. We will also explore the hypothesis that a primary biologic effect of cytokines such as TNFalpha and IL-1 is upregulation of these adhesion molecules. To address this we will determine if direct infusion of these cytokines induces upregulation of adhesion molecules in glomeruli and also conversely if specific antibodies to these cytokines inhibits the glomerular injury by preventing the upregulation of these molecules. In correlative in vitro studies we will determine if inflammatory mediators such as oxygen radicals and cytokines upregulate ELAM-1, VCAM-1, and ICAM-1 on mesangial and endothelial cells in culture. In addition, we will determine if oxidants upregulate integrin expression on neutrophils and monocytes and the effect of the leukocyte integrin antibodies; anti-CD18 and CD11b on leukocyte dependent killing of endothelial and mesangial cells. Our preliminary studies show that mesangial cells express adhesion molecules similar to the endothelial cells and that these adhesion molecules are important not only for adherence but also for leukocyte mediated cytotoxicity. The proposed studies as outlined above should provide new and useful information on the role of adhesion molecules in glomerulonephritis. If in fact adhesion molecules turn out to be as important in the pathogenesis of this disease as our preliminary studies suggest then specific """"""""anti-adhesion"""""""" therapy using monoclonal; antibodies could have a beneficial effect in the treatment of glomerulonephritis.
| Hato, Takashi; Winfree, Seth; Day, Richard et al. (2017) Two-Photon Intravital Fluorescence Lifetime Imaging of the Kidney Reveals Cell-Type Specific Metabolic Signatures. J Am Soc Nephrol 28:2420-2430 |
| Kikuchi, Masao; Wickman, Larysa; Hodgin, Jeffrey B et al. (2015) Podometrics as a Potential Clinical Tool for Glomerular Disease Management. Semin Nephrol 35:245-55 |
| Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28 |
| Fukuda, Akihiro; Wickman, Larysa T; Venkatareddy, Madhusudan P et al. (2012) Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker. Nephrol Dial Transplant 27:4079-87 |
| Fukuda, Akihiro; Wickman, Larysa T; Venkatareddy, Madhusudan P et al. (2012) Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease. Kidney Int 81:40-55 |
| Wiggins, Jocelyn E (2012) Aging in the glomerulus. J Gerontol A Biol Sci Med Sci 67:1358-64 |
| Fukuda, Akihiro; Chowdhury, Mahboob A; Venkatareddy, Madhusudan P et al. (2012) Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol 23:1351-63 |
| Chernin, Gil; Vega-Warner, Virginia; Schoeb, Dominik S et al. (2010) Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin J Am Soc Nephrol 5:1655-62 |
| Chernin, Gil; Heeringa, Saskia F; Vega-Warner, Virginia et al. (2010) Adequate use of allele frequencies in Hispanics--a problem elucidated in nephrotic syndrome. Pediatr Nephrol 25:261-6 |
| Kim, Doyeob; Patel, Sanjeevkumar R; Xiao, Hong et al. (2009) The role of PTIP in maintaining embryonic stem cell pluripotency. Stem Cells 27:1516-23 |
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