1. Quercetin alleviates cadmium chloride-induced renal damage in rats by suppressing endoplasmic reticulum stress through SIRT1-dependent deacetylation of Xbp-1s and eIF2α.
- Author
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Alshammari GM, Al-Qahtani WH, AlFaris NA, Albekairi NA, Alqahtani S, Eid R, Yagoub AEA, Al-Harbi LN, and Yahya MA
- Subjects
- Animals, Carbazoles pharmacology, Cytokines antagonists & inhibitors, Cytokines metabolism, Dose-Response Relationship, Drug, Kidney Function Tests, Male, Rats, Rats, Wistar, Reactive Oxygen Species metabolism, Sirtuin 1 antagonists & inhibitors, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antioxidants therapeutic use, Cadmium Chloride, Endoplasmic Reticulum Stress drug effects, Eukaryotic Initiation Factor-2 metabolism, Kidney Diseases chemically induced, Kidney Diseases drug therapy, Quercetin therapeutic use, Sirtuin 1 drug effects, X-Box Binding Protein 1 metabolism
- Abstract
Endoplasmic reticulum (ER) stress plays a key role in cadmium chloride (CdCl2)-induced nephrotoxicity. Sirtuin-1 (SIRT1) is a potent inhibitor of ER stress. In this study, we examined whether the protective effect of quercetin (QUR) against CdCl
2 -induced nephrotoxicity in rats involved modulation of SIRT1 and/or ER stress. Adult male rats were divided into five groups (n = 8, each) and treated for eight weeks as follows: control, control + QUR, CdCl2 , CdCl2 + QUR, and CdCl2 + QUR + EX-527 (a SIRT1 inhibitor). Treatment of rats with QUR preserved the glomerulus and tubule structure, attenuated interstitial fibrosis, increased creatinine excretion, and reduced urinary levels of albumin, N-acetyl-β-D-glucosaminidase, and β2-microglobulin in CdCl2 -treated rats. Concomitantly, QUR increased renal levels of Bcl-2, reduced mRNA levels of CHOP, and protein levels of Bax, caspase-3, and cleaved caspase-3, but failed to reduce the mRNA levels of GRP78, PERK, eIf2α, ATF-6, and xbp-1. QUR also reduced the renal levels of reactive oxygen species, tumour necrosis factor, and interleukin-6 and the nuclear activity of NF-κB in the control and CdCl2 -treated rats but increased the nuclear activity of Nrf2 and levels of glutathione and manganese superoxide dismutase. Additionally, QUR increased the total levels and nuclear activity of SIRT1 and reduced the acetylation of eIf2α and xbp-1. The nephroprotective effects of QUR were abrogated by treatment with EX-527. Thus, QUR ameliorated CdCl2 -induced nephrotoxicity through antioxidant and anti-inflammatory effects and suppressed ER stress mediated by the upregulation or activation of SIRT1-induced deacetylation of Nrf2, NF-κB p65, eIF2α, and xbp-1., (Copyright © 2021. Published by Elsevier Masson SAS.)- Published
- 2021
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