(provided by candidate): Focal segmental glomerulosclerosis (FSGS) is characterized by heavy proteinuria and progression to end-stage renal disease. The incidence of FSGS has increased markedly over the past 20 years, and is the most common cause of primary nephrotic syndrome in adults in several series. The cyclooxygenase inhibitor indomethacin decreases proteinuria in patients with FSGS, implicating a product of arachidonic acid metabolism as a mediator of proteinuria. A low molecular weight protein in plasma of patients with FSGS (referred to as the FSGS factor) increases albumin permeability of isolated glomeruli. Presence of the FSGS factor is associated with and predictive of recurrence of disease in renal allografts. Work funded by my K08 grant demonstrated that the FSGS factor increases glomerular albumin permeability by stimulating the arachidonic acid cyclooxygenase and thromboxane A-2 synthase pathways. Also, the FSGS factor releases arachidonic acid from isolated glomeruli and stimulates prostaglandin EZ synthesis. In preliminary studies, I have shown increased expression of phospholipase A-2, cyclooxygenase-2 (COX-2) and thromboxane A-2 synthase in kidneys of rats injected with the FSGS factor. The proposed studies will further explore this effect.
The Specific Aim i s to determine whether the FSGS factor alters in vivo glomerular expression of key enzymes of arachidonic acid metabolism. Rats will be injected with the FSGS factor or an identical fraction of normal plasma. Kidney tissue (kidney slices or isolated glomeruli) will be examined at various time points for mRNA and protein levels of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase using Western blotting and RT-PCR. Results will be correlated with glomerular albumin permeability and with urinary excretion of protein and eicosanoids. Results of the proposed experiments will provide the groundwork for further studies to explore transcriptional regulation of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase by the FSGS factor. These studies will provide insight into the pathophysiology of proteinuria in patients with recurrent FSGS and may lead to novel treatment strategies in these patients.
| Sharma, Mukut; McCarthy, Ellen T; Reddy, D Sudarshan et al. (2009) 8,9-Epoxyeicosatrienoic acid protects the glomerular filtration barrier. Prostaglandins Other Lipid Mediat 89:43-51 |
| Sharma, Mukut; McCarthy, Ellen T; Sharma, Ram et al. (2006) Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability. Exp Biol Med (Maywood) 231:99-106 |
| Dahly-Vernon, Annette J; Sharma, Mukut; McCarthy, Ellen T et al. (2005) Transforming growth factor-beta, 20-HETE interaction, and glomerular injury in Dahl salt-sensitive rats. Hypertension 45:643-8 |
| Sharma, Mukut; McCarthy, Ellen T; Savin, Virginia J et al. (2005) Nitric oxide preserves the glomerular protein permeability barrier by antagonizing superoxide. Kidney Int 68:2735-44 |
