Hemolytic uremic syndrome is a clinical syndrome characterized by renal failure, thrombocytopenia, and nonimmune hemolytic anemia. Although there appear to be diverse causes, all have in common the glomerular endothelium (GEN) as the principal site of injury. Whereas, the acute survival of patients with HUS has improved dramatically, a vexing problem still remains, i.e., the long term complications, with 20-40% of individuals developing renal impairment due to progressive glomerulosclerosis. Our basic hypothesis is that progressive glomerular disease results from the inadequate repair of the GEN following injury. Our application therefore, focuses on how the GEN recovers from acute injury, particularly as it relates to the growth factors and cell cycle proteins which are important in the initial recovery and proliferation of the GEN population.
In first aim we will study the role of four growth factors in the GEN proliferative response in a rat model of HUS, by identifying the kinetics and magnitude of their expression in relation to GEN proliferation, total GEN cellularity and apoptosis, and by examining the consequences of blocking these growth factors on the GEN proliferation and other structural and functional parameters. In the second aim we will concentrate on the cell cycle proteins involved in the GEN proliferative response both in vitro (using mouse and rat GEN) and in vivo (using murine and rat models of HUS). Based on preliminary data in other models, we will also investigate the functional role of two cyclin kinase inhibitors (p21 and p27) in the GEN proliferative and apoptotic response in mice lacking these proteins (knockouts). Once the mechanisms for GEN proliferation and recovery have been elucidated, potentially new therapeutic strategies can be developed to prevent the crippling long-term complications of this disease.
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