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Effects of FSGS factor on arachidonic acid metabolism

FSGS因子对花生四烯酸代谢的影响

基本信息

批准号：
6623268
负责人：
ELLEN T MCCARTHY
金额：
$ 7.5万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6623268
关键词：
clinical research eicosanoid metabolism enzyme activity glomerulosclerosis human subject laboratory rat pathologic process phospholipase A2 polymerase chain reaction prostaglandin endoperoxide synthase proteins thromboxanes

项目摘要

DESCRIPTION (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 is 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.

描述（由候选人提供）：