The long-term goal of our studies is to unravel the cellular and molecular complexities of renal fibrosis with a view to identifying new therapeutic targets that can prevent or even reverse progressive renal disease. It is likely that major advances in the treatment of patients with chronic renal failure will entail new therapeutic agents that target several key molecules in the fibrogenic pathway, akin to chemotherapy for cancer. Our recent studies suggest that urokinase (uPA) and its receptors regulate pathophysiological responses of the kidney to chronic injury, serving to attenuate the severity of fibrosis, renal structural damage and loss of renal function.
Five specific aims studies will continue to investigate how the cellular and proteolytic actions of uPA and its receptors modulate renal fibrogenesis.
Aim #1 will determine if and how the proteolytic enzyme uPA modulates renal fibrosis by investigating experimental models in mice with a genetic deficiency of uPA or with macrophages that over-express uPA in comparison to wild-type mice.
Aim #2 will investigate the role of the macrophage urokinase receptor (uPAR) in renal inflammation and fibrogenesis using bone marrow transplantation strategies to generate chimeric mice (uPAR wild-type mice with uPAR-deficient macrophages and visa versa).
Aim #3 will investigate the role of the uPAR scavenger co-receptor, lowdensity lipoprotein receptor-related protein (LRP), in the renal fibrogenic response using genetically engineered mice lacking LRP-expressing macrophages or fibroblasts.
Aim #4 will investigate the role of the uPAR-LRP ligand plasminogen activator inhibitor-1 (PAl-1) in the tubulointerstitial response to renal injury.
Aim #5 will seek to identify the alternative (non-uPAR) uPA receptor that stimulates kidney fibroblast proliferation. The proposed studies are designed to investigate the hypothesis that the fibrogenic response to renal injury in vivo is attenuated by uPA working as an extracellular protease to enhance degradation of matrix proteins (eg; fibrinogen, fibronectin) directly or indirectly (via activation of plasminogen, latent metalloproteinases or hepatocyte growth factor). It is further hypothesized that uPA also acts via specific cellular receptor(s) to modulate the recruitment and function of cells at the site of renal injury. In particular it is proposed that uPAR promotes macrophage recruitment and together with its co-receptor LRP, provides macrophages with an efficient vacuuming mechanism to eliminate pro-fibrotic molecules such as PAl-1 and protease nexin-1. Finally an alternative as yet unidentified uPA receptor that is up-regulated in the absence of uPAR is proposed to stimulate fibroblast proliferation. The identity of this receptor will be pursued.
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| Ricardo, Sharon D; van Goor, Harry; Eddy, Allison A (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522-30 |
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