Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5827072 | European Journal of Pharmacology | 2015 | 7 Pages |
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 (20Â mg/kg). Markers of ER stress were studied in the kidneys 1, 12 and 24Â h later. GRP78, p-PERK and nuclear sXBP-1, all markers of ER stress, were found to be increased in the rat kidney at 12Â h, in response to indomethacin; levels of these markers fell by 24Â h. The effects seen at 12Â h 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.
Keywords
PARPATF4ATF6eIF2αNSAIDNrf2HO-1IRE1Cyt CROSinositol-requiring enzyme 1ER stressEndoplasmic reticulum stressIndomethacinCHOPApoptosiscytochrome cNon-steroidal anti-inflammatory drugactivating transcription factor-4activating transcription factor-6Zincglucose-regulated protein 78PERKpoly-ADP ribose polymeraseKidneyGrp 78Reactive oxygen species
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Authors
Arumugam Suriyam Nagappan, Joe Varghese, Jithu V. James, Molly Jacob,