Glomerulonephritides (GN) are associated with leukocyte migration and resident glomerular cell proliferation. Adhesion molecules are implicated in these processes. The objective of this proposal is to assess the effect of deficiencies in select leukocyte adhesion receptors and the extracellular matrix molecule thrombospondin on renal injury in murine models of glomerulonephritis developed by our group: acute, passive anti- glomerular basement membrane nephritis, complement dependent acute nephrotoxic serum nephritis and accelerated nephrotoxic serum nephritis associated with cellular proliferation, mesangial sclerosis and massive proteinuria. To accomplish these studies we have in a collaborative effort, or have generated using gene targeting technology, mice deficient in leukocyte adhesion receptors, selectins (P-, E-, P- and E-, and L- selectin), ICAM-1, ICAM-1 and P-selectin, Mac-1, and mice deficient in thrombospondin 1. The selectins support leukocyte rolling and loose adhesion on the venular endothelium which is a prerequisite to firm adhesion promoted by members of the leukocyte beta2 integrins (e.g., Mac- 1) and IgG superfamily (e.g., ICAM-1). However, the relevance of the paradigm of leukocyte rolling, firm adhesion and extravasation examined in a limited number of tissues, to the specialized microvasculature of the glomeruli remains controversial. Thrombospondin, an extracellular matrix molecule is a potent stimulator of mesangial cell proliferation in vitro although the in vivo implications of this have not been extensively studied. Our working hypothesis is that leukocyte adhesion molecules and thrombospondin play a pivotal role in glomerular hypercellularity by mediating leukocyte infiltration and resident glomerular cell proliferation respectively. In support of our hypothesis, we have found that acute, passive anti-glomerular basement membrane nephritis in mice deficient in P-selectin, an endothelial and platelet selectin, leads to increased glomerular neutrophil influx and markedly higher urine proteinuria compared to wild-type mice. Our studies further demonstrated a role for P-selectin mediated platelet-neutrophil interaction in GN in the transcellular biosynthesis of lipoxin A4, previously proposed as a potent """"""""stop-signal"""""""" for neutrophil influx (preliminary results). Knock- outs remain a powerful adjunct to understanding the role of adhesion molecules in inflammatory disease and will contribute to a comprehensive understanding of the role of leukocyte adhesion molecules and thrombospondin in glomerulonephritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051643-02
Application #
2458944
Study Section
Pathology A Study Section (PTHA)
Project Start
1996-08-20
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Venkatesh, Deepak; Ernandez, Thomas; Rosetti, Florencia et al. (2013) Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-? autocrine signaling to promote monocyte recruitment. Immunity 38:1025-37
Sehrawat, Seema; Ernandez, Thomas; Cullere, Xavier et al. (2011) AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties. Blood 117:708-18
Vielhauer, Volker; Mayadas, Tanya N (2007) Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue injury and immune regulation. Semin Nephrol 27:286-308
Hirahashi, Junichi; Mekala, Divya; Van Ziffle, Jessica et al. (2006) Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25:271-83
Liu, Zhi; Zhao, Minglang; Li, Ning et al. (2006) Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid. Blood 107:1063-9
Vielhauer, Volker; Stavrakis, George; Mayadas, Tanya N (2005) Renal cell-expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis. J Clin Invest 115:1199-209
Hochegger, Kathrin; Knight, Sara; Hugo, Christian et al. (2004) Role of thrombospondin-1 in the autologous phase of an accelerated model of anti-glomerular basement membrane glomerulonephritis. Nephron Exp Nephrol 96:e31-8
Stokol, Tracy; O'Donnell, Peter; Xiao, Ling et al. (2004) C1q governs deposition of circulating immune complexes and leukocyte Fcgamma receptors mediate subsequent neutrophil recruitment. J Exp Med 200:835-46
Coxon, A; Cullere, X; Knight, S et al. (2001) Fc gamma RIII mediates neutrophil recruitment to immune complexes. a mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity 14:693-704
Barkalow, F J; Barkalow, K L; Mayadas, T N (2000) Dimerization of P-selectin in platelets and endothelial cells. Blood 96:3070-7

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