Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP142) Ibuprofen prevents the early effects of ionizing radiation on normal glomeruli.

Sharma, Mukut 1, McCarthy, Ellen1, Sharma, Ram1, Fish, Brian2, Savin, Virginia 1, Cohen, Eric1, Moulder, John*,2, 1 Nephrology Division, Milwaukee, WI, USA2 Department of Radiation Oncology, Milwaukee, WI, USA

ABSTRACT- Radiation-induced renal injury is characterized at fairly advanced stages by proteinuria and hypertension. Identification and characterization of early indicators of renal injury will facilitate mitigation and treatment of radiation nephropathy. We have 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 one hour. The current studies tested the hypothesis that the radiation-induced increase in P alb can be blocked or reversed by ibuprofen, a clinically used non-steroidal anti-inflammatory drug that inhibits cyclooxygenase (COX)-1 and 2 at about equimolar concentrations. We irradiated glomeruli from WAG/Rij/MCW rats with 9.5 Gy (single dose) in a 137cesium gamma-ray generator (JL Shepherd Model 137). Sham-irradiated glomeruli were used as controls. First, we demonstrated that irradiation of isolated glomeruli causes release of arachidonic acid (AA). Glomeruli were pre-labeled with (3H)-arachidonic acid (1h) and then irradiated (9.5 Gy, single dose). Radioactivity measurement showed that the release of (3H)-AA and its metabolites (cpm/mg protein) was increased by 180% and 67% at 10 and 60 min after irradiation, respectively. Next, isolated glomeruli were incubated with ibuprofen (20 M) for 30 min prior to or within 2 min after irradiation and Palb measured at 1h post-irradiation. Pre-incubation with ibuprofen completely blocked the increase in Palb (0.1± 0.06, n=15 vs. 0.74±0.08, n=15, P <0.001). Addition of ibuprofen immediately after irradiation also partially blocked the increase in Palb (0.28± 0.06, n=15 vs. 0.74± 0.08, n=15, P <0.01). Finally, we confirmed the effect of COX inhibition by showing that two other COX-inhibitors, indomethacin (Palb 0.09± 0.03, n=15, P < 0.001) and acetyl salicylic acid (Palb 0.22± 0.07, n=20, P <0.001) also blocked the radiation-induced increase in P alb (0.65±0.01, n=20). Parallel experiments showed that quinacrine, an inhibitor of phospholipase A sub>2 that catalyzes the release of AA from phospholipids, also prevented the radiation-induced increase in P alb (0.16± 0.03, n=15; P <0.001). We conclude that AA and its COX-metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P alb. ≤

Key words: radiation nephropathy, glomerular albumin permeability, arachidonic acid, normal tissue injury

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2005 RRS