application) Focal segmental glomerulosclerosis (FSGS) is a renal disease of unknown etiology characterized by heavy proteinuria, hypertension, and progression to renal failure. The incidence of FSGS has increased by up to 8-fold in the past 20 years. It is the now the most common progressive glomerular disease in children and account for 20_25% of nephrotic syndrome in adults. Cyclooxygenase (COX) inhibitors decrease proteinuria in many proteinuric glomerular disease, including FSGS. The applicant has participated in studies that document the presence of a plasma factor in patients with FSGS which causes an increase in glomerular albumin permeability. In preliminary studies, she has shown that the COX inhibitor indomethacin prevented the increased in albumin permeability caused by the FSGS factor, thus implicating eicosanoids of the COX pathways of arachidonic acid metabolism as mediators of this effect. In the proposed studies, she will determine the role of these eicosanoids in mediating the increased glomerular protein permeability caused by the FSGS factor, and explore mechanisms by which this factor regulated synthesis of COX-derived eicosanoids. Hypothesis to be tested are: (1) the FSGS factor increased synthesis of specific eicosanoids of the COX pathway, and these eicosanoids increase glomerular albumin permeability; (2) the FSGS factor increases synthesis of COX-derived eicosanoids via an effect on activity and/or expression of phospholipase A2 (PLA2), constitutive COX or inducible COX. She will measure eicosanoid production by isolated glomeruli or cultured glomerular cells after incubation with the FSGS factor and will then determine the effect of eicosanoids identified in these studies, on glomerular albumin permeability. Finally, she will investigate the mechanism by which the FSGS factor enhance eicosanoid synthesis by measuring activity and expression (mRNA and protein) of PLA, and of constitutive and inducible COX in glomeruli and in cultured glomerular cells. The proposed project is expected to provide the applicant with valuable opportunities to expand hew knowledge and expertise in experimental design, investigative techniques, and data analysis. Results of these studies will provide insight into the pathophysiology of FSGS. Additionally, they may lead to a better understanding of the general mechanism by which proteinuria develops and thus point to interventions that may alleviate or prevent proteinuria in FSGS and in other glomerular diseases.
|Savin, Virginia J; McCarthy, Ellen T; Sharma, Mukut (2003) Permeability factors in focal segmental glomerulosclerosis. Semin Nephrol 23:147-60
|McCarthy, Ellen T; Sharma, Mukut (2002) Indomethacin protects permeability barrier from focal segmental glomerulosclerosis serum. Kidney Int 61:534-41
|Sharma, M; Sharma, R; Ge, X L et al. (2001) Early detection of radiation-induced glomerular injury by albumin permeability assay. Radiat Res 155:474-80