title: All-trans retinoic acid potentiates cisplatin-induced kidney injury in rats: impact of retinoic acid signaling pathway.
abstract: Cisplatin (cis-diammine dichloroplatinum (II), CDDP) is a widely used drug for treatment of various types of cancers. However, CDDP-induced nephrotoxicity remains the main dose-limiting side effect. Retinoids are a group of vitamin A-related compounds that exert their effects through retinoid receptors activation. In this study, we investigated the effect of CDDP treatment on retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α) expression. In addition, we investigated the possible modulatory effects of RAR agonist, all-trans retinoic acid (ATRA), on CDDP-induced nephrotoxicity. Rats were treated with saline, DMSO, CDDP, ATRA, or CDDP/ATRA. Twenty-four hours after the last ATRA injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CDDP treatment significantly increased serum levels of creatinine and urea, with concomitant decrease in serum albumin. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CDDP treatment. Furthermore, CDDP markedly upregulated tubular RAR-α, RXR-α, fibrin, and inducible nitric oxide synthase (iNOS) protein expression. Although administration of ATRA to control rats did not produce marked alterations in kidney function parameters, administration of ATRA to CDDP-treated rats significantly exacerbated CDDP-induced nephrotoxicity. In addition, CDDP/ATRA co-treatment significantly increased RAR-α, RXR-α, fibrin, and iNOS protein expression compared to CDDP alone. In conclusion, we report, for the first time, the crucial role of retinoid receptors in CDDP-induced nephrotoxicity. Moreover, our findings indicate that co-administration of ATRA with CDDP, although beneficial on the therapeutic effects, their deleterious effects on the kidney may limit their clinical use.
authors.affiliation: Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Abdelrahman M
authors.initials: AM
authors.lastname: Elsayed
authors.affiliation: Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. tamer_ibrahim2@yahoo.com.
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Abdelghany
authors.affiliation: Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: El-Sayed
authors.initials: el-S
authors.lastname: Akool
authors.affiliation: Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Abdel-Aziz H
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.affiliation: Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.|College of Pharmacy, Aljouf University, Sakaka, Aljouf, 2014, Kingdom of Saudi Arabia.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Bakky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D004357:Drug Synergism; D005337:Fibrin / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014212:Tretinoin; D005337:Fibrin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D002945:Cisplatin
keywords: All-trans retinoic acid; Cisplatin nephrotoxicity; Fibrin; Inducible nitric oxide synthase; Retinoic acid receptor alpha; Retinoid X receptor alpha