title: 8,9-Epoxyeicosatrienoic acid protects the glomerular filtration barrier.
abstract: Glomerular dysfunction and proteinuria characterize focal segmental glomerulosclerosis (FSGS) associated with chronic kidney disease. FSGS is resistant to treatment and a circulating permeability factor (FSPF) frequently causes post-renal transplantation recurrence. In order to explore the role of 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acids (EETs), we determined their effect on FSPF-induced increase in glomerular albumin permeability (P alb) using an in vitro assay. Exogenous 8,9-EET (1-1000 nM) dose-dependently prevented the FSPF-induced increase in P alb. The other three EET regioisomers, 8,9-EET metabolite, 8,9-dihydroxyeicosatrienoic acid and unrelated 11,14-eicosadienoic acid (100 nM each) were not effective suggesting specificity of the observed glomerular protection by 8,9-EET. Synthetic analogs of 8,9-EET containing one double bond antagonized the effect of 8,9-EET on the FSPF-induced increase in P alb. Analogs containing two double bonds did not antagonize the effect of 8,9-EET and significantly blocked the FSPF-induced increase in P alb. These novel findings suggest a unique protective role for 8,9-EET in the glomerulus. Stable analogs of 8,9-EET may be valuable in developing effective management/treatment of glomerular dysfunction.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. msharma@mcw.edu
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.forename: Ellen T
authors.initials: ET
authors.lastname: McCarthy
authors.forename: D Sudarshan
authors.initials: DS
authors.lastname: Reddy
authors.forename: Paresh K
authors.initials: PK
authors.lastname: Patel
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Savin
authors.forename: Meetha
authors.initials: M
authors.lastname: Medhora
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D012709:Serum Albumin; D014665:Vasodilator Agents; C050715:8,9-epoxyeicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid