Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability.
Radiation-induced renal injury is characterized by proteinuria, hypertension, and progressive decline in renal function. We have previously shown that in vivo or in vitro irradiation of glomeruli with a single dose of radiation (9.5 Gy) increases glomerular albumin permeability (P(alb)) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in P(alb) is caused by the release of arachidonic acid and by the generation of specific arachidonic acid metabolites. Glomeruli obtained from WAG/Rij/MCW rats and cultured rat glomerular epithelial and mesangial cells were studied after irradiation (9.5 Gy, single dose). Arachidonic acid release and eicosanoid synthesis by glomeruli or cultured glomerular cells were measured after irradiation, and the effect of inhibitors of phospholipase A2 (PLA2) and cyclooxygenase (COX) on the irradiation-induced increase in P(alb) was assessed. Arachidonic acid release was demonstrated within 10 mins of irradiation of isolated glomeruli and monolayer cultures of glomerular epithelial and mesangial cells. Prostaglandin F(2alpha) (PGF(2alpha)) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in P(alb). COX inhibition immediately after irradiation also diminished the radiation-induced increase in P(alb). We conclude that arachidonic acid and its COX metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P(alb). Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.
Sharma
Mukut
M
Division of Nephrology and the Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. msharma@mcw.edu
McCarthy
Ellen T
ET
Sharma
Ram
R
Fish
Brian L
BL
Savin
Virginia J
VJ
Cohen
Eric P
EP
Moulder
John E
JE
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D044127:Epigenesis, Genetic; D004847:Epithelial Cells; D007678:Kidney Glomerulus / Q000378:metabolism / Q000528:radiation effects*; D050527:Mesangial Cells; D010539:Permeability / Q000528:radiation effects*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D054467:Phospholipases A2; D011833:Radiation Injuries, Experimental / Q000378:metabolism*; D051381:Rats; D014916:Whole-Body Irradiation
D000418:Albumins; D052246:Cyclooxygenase 2 Inhibitors; D015777:Eicosanoids; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone