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Experimental Biology and Medicine 231:99-106 (2006)
© 2006 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Arachidonic Acid Metabolites Mediate the Radiation-Induced Increase in Glomerular Albumin Permeability

Mukut Sharma*,1, Ellen T. McCarthy*, Ram Sharma*, Brian L. Fish{dagger}, Virginia J. Savin*, Eric P. Cohen* and John E. Moulder{dagger}

* Division of Nephrology and the Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and {dagger} Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

To whom requests for reprints should be addressed at 1 Rm. M4040, Nephrology/CVC/MEB, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: msharma{at}mcw.edu

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 (Palb) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in Palb 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 Palb 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 F2{alpha} (PGF2{alpha}) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in Palb. COX inhibition immediately after irradiation also diminished the radiation-induced increase in Palb. 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 Palb. Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.

Key Words: radiation nephropathy • normal tissue injuries • epigenetic changes • proteinuria • glomerular function • albumin permeability • arachidonic acid • eicosanoids • cyclooxygenase






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