Fibrin formation in the glomerulus is an important event in a wide variety of clinical conditions which include Rapidly Progressive Glomerulonephritis (RPGN), Hemolytic Uremic and Thrombotic Thrombocytopenic Purpura syndromes, Postpartum Renal Failure and Disseminated Intravascular Coagulation following septicemias and malignancy. In RPGN fibrin formation in Bowman's space has been shown to be an essential step in the sequence of events leading to macrophage immigration and subsequent fibroblast proliferation and collagen formation leading to renal failure. This application sets out a series of studies planned to work out which cells produce procoagulant and fibrinolytic activity, when these activities occur during the sequence of events leading to RPGN, and how they might be regulated. These will include: (a) Isolating macrophages from glomeruli obtained at various times during crescent development in a model of nephrotoxic nephritis in the rabbit and measuring their capacity to produce procoagulant and plasminogen-activating activity; (b) Using well characterized cells cultured from human glomeruli to identify which cells intrinsic to the glomerulus have the capability of producing procoagulant and fibrinolytic activity and how this is regulated; (c) Measuring the consequences of inhibition fibrinolytic activity by administration of E-ACA in the model of crescentic nephritis in the rabbit; (d) Characterizing the chemotactic signals for macrophages produced by glomeruli isolated at various times during development of crescentic nephritis in the rabbit. (e) Analyzing the procoagulant mechanism operating in the subcellular particles which carry the procoagulant activity in urine, and identify where in the urinary tract they are coming from by using purified proteins of the rabbit coagulation system and by developing a monoclonal antibody against rabbit tissue factor. The results of these studies will provide the necessary information regarding which cells in the glomerulus have procoagulant and fibrinolytic potential, how they can be regulated, what is the likely macrophage contribution to those mechanisms, and how important those mechanisms are in changing a relatively minor glomerular injury into crescent development with its severe prognostic implications. By understanding these events it may become possible to manipulate a major risk factor in the development of glomerular injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK030673-04A1
Application #
3229587
Study Section
Pathology A Study Section (PTHA)
Project Start
1982-02-01
Project End
1988-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109