Indomethacin induces free radical-mediated changes in renal brush border membranes

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in clinical medicine. One disadvantage of their use, however, is the occurrence of adverse effects in the kidneys. The side effects produced in this organ have been classically attributed to the inhibitory effect of these drugs on the activity of cyclooxygenase, a key enzyme in prostaglandin synthesis. Our earlier work with indomethacin, a commonly used NSAID, has shown that oxidative stress and mitochondrial dysfunction occur in the kidney in response to the drug. In view of this, this study looked into the effect of indomethacin on brush border membranes (BBM) from the kidney, as these biomembranes are prime targets of oxygen free radicals. Rats, fasted overnight, were dosed with indomethacin (20 mg/kg) by gavage and sacrificed 24 h later. BBM were isolated from the kidneys by polyethylene glycol precipitation. It was found that there was an increase in levels of products of peroxidation and a fall in the level of alpha-tocopherol in the BBM from indomethacin-dosed rats. These BBM also exhibited impaired glucose transport. The lipid composition of the membranes was also found to be altered. Alterations in lipids were associated with up-regulation of phospholipase A₂. Pretreatment with L-arginine, a nitric oxide donor, protected against these effects of indomethacin. Thus, this study suggests that indomethacin induces impairment in structure and function of BBM in the kidney, with these effects possibly mediated by free radicals and activation of phospholipases. We postulate that such alterations may be important in the pathogenesis of NSAID-induced nephropathy.