title: Indomethacin induces endoplasmic reticulum stress, but not apoptosis, in the rat kidney.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice. However, their use is often associated with adverse effects in the gastrointestinal tract and kidney. Our earlier work with indomethacin, a prototype NSAID, has shown that it induced oxidative stress in the kidney in rats, an event that has been postulated to contribute to pathogenesis of its adverse effects in this organ. Endoplasmic reticulum (ER) stress responses have been shown to occur in response to oxidative stress. We investigated whether this occurred in the rat kidney, in response to indomethacin. For this, Wistar rats were orally gavaged with indomethacin (20mg/kg). Markers of ER stress were studied in the kidneys 1, 12 and 24h later. GRP78, p-PERK and nuclear sXBP-1, all markers of ER stress, were found to be increased in the rat kidney at 12h, in response to indomethacin; levels of these markers fell by 24h. The effects seen at 12h were attenuated by pre-treatment with zinc, a known anti-oxidant, which has earlier been shown to ameliorate indomethacin-induced oxidative stress. Activation of an ER stress response was not associated with induction of apoptosis, as measured by markers of apoptosis such as release of cytochrome c from mitochondria into the cytosol, activation of caspases 3 and 9, cleavage of poly-ADP ribose polymerase and the presence of DNA laddering. We conclude that indomethacin-induced oxidative stress activated ER stress, but did not lead to apoptosis in the rat kidney.
authors.affiliation: Department of Biochemistry, Christian Medical College, Vellore 632002, India. Electronic address: aruarum@gmail.com.
authors.forename: Arumugam Suriyam
authors.initials: AS
authors.lastname: Nagappan
authors.affiliation: Department of Biochemistry, Christian Medical College, Vellore 632002, India. Electronic address: joevarghese@cmcvellore.ac.in.
authors.forename: Joe
authors.initials: J
authors.lastname: Varghese
authors.affiliation: Department of Biochemistry, Christian Medical College, Vellore 632002, India.
authors.forename: Jithu V
authors.initials: JV
authors.lastname: James
authors.affiliation: Department of Biochemistry, Christian Medical College, Vellore 632002, India. Electronic address: mjacob@cmcvellore.ac.in.
authors.forename: Molly
authors.initials: M
authors.lastname: Jacob
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D006360:Heat-Shock Proteins; D007213:Indomethacin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
keywords: Apoptosis; ER stress; Indomethacin; Kidney; Zinc