Indomethacin-induced renal damage: role of oxygen free radicals.
Nonsteroidal anti-inflammatory drugs are used extensively in clinical medicine. In spite of their therapeutic utility, however, they are known to cause significant gastrointestinal and renal toxicities, circumstances that limit their use. The side effects produced in these organs have been attributed mainly to the inhibitory effect of these drugs on the activity of cyclooxygenase, a key enzyme in prostaglandin synthesis. In addition to this, in the small intestine it is known that reactive oxygen species also contribute to the enteropathy seen in response to these drugs. In the kidney, however, there is little information whether other mechanisms contribute to the renal toxicity. This study was designed to look at the possible biochemical mechanisms involved in indomethacin-induced renal damage. Rats fasted overnight were dosed with indomethacin (20 mg/kg) by gavage and sacrificed 24 hr later. Histology of the kidney showed abnormalities in the mitochondria in the proximal tubules. Evidence of oxidative stress was found in the kidney associated with mitochondrial dysfunction and neutrophil infiltration. The lipid composition in the mitochondria was also altered. Such effects were abolished by the prior administration of arginine, a donor of nitric oxide. This study, thus, suggests that one of the mechanisms by which nonsteroidal anti-inflammatory drugs induce renal damage is through oxygen free radicals possibly generated by activated neutrophils and mitochondrial dysfunction.
Basivireddy
Jayasree
J
The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore 632004, India.
Jacob
Molly
M
Pulimood
Anna B
AB
Balasubramanian
Kunissery A
KA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D005609:Free Radicals / Q000378:metabolism; D007213:Indomethacin / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005609:Free Radicals; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D007213:Indomethacin