Augmented nephroprotective effect of liraglutide and rabeprazole via inhibition of OCT2 transporter in cisplatin-induced nephrotoxicity in rats

• Published in: Life sciences (1973) 2023-05, Vol.321, p.121609-121609, Article 121609
• Main Authors: Sharaf, Gehad, E.M., El Morsy, El-Sayed, Elsayed K.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cisplatin; Cisplatin - metabolism; Cisplatin - toxicity; Kidney - metabolism; Liraglutide; Liraglutide - metabolism; Liraglutide - pharmacology; MAPK; Mitogen-Activated Protein Kinases - metabolism; Nephrotoxicity; OCT2 and GLP-1; Oxidative Stress; Rabeprazole; Rabeprazole - pharmacology; Rats
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2023.121609

Cisplatin, a widely used anticancer treatment, has a marked nephrotoxic effect. This nephrotoxic effect is linked to the triggering of oxidative stress, inflammation, activation of mitogen-activated protein kinase (MAPK) pathway as well as apoptosis. The purpose of the present research was to examine the possible ameliorative effect of liraglutide and/or rabeprazole on cisplatin-induced nephrotoxicity in rats and to underline the potential molecular pathways involved. Rats were divided into five groups: Control, cisplatin, liraglutide (200 μg/kg/day, i.p), rabeprazole (10 mg/kg/day, orally) and liraglutide + rabeprazole combination groups. All treatments were given for 7 days. Cisplatin was given as a single dose (7 mg/kg, i.p) at day 4 to induce nephrotoxicity in all groups except the control group. Treatment with liraglutide and/or rabeprazole prior to cisplatin maintained the function and morphology of kidney via decreasing cisplatin renal uptake by significant inhibition of OCT2. Besides, they showed a significant increase in GLP-1 receptor expression. Liraglutide and/or rabeprazole significantly attenuated the levels of TNF-α. ICAM, NF-κB, and downregulated MAPK pathway proteins such as JNK, and ERK1/2. Moreover, they maintained oxidant antioxidant balance by decreasing MDA level and increasing GSH level and CAT activity. Additionally, liraglutide and/or rabeprazole exhibited antiapoptotic effect evidenced by the decreased caspase-3 level and Bax expression and the increased Bcl-2 expression. The current study showed that both liraglutide and rabeprazole exerted a nephroprotective effect against cisplatin-induced renal toxicity in rats. Interestingly, co-treatment with both drugs showed an augmented effect. •Liraglutide and Rabeprazole ameliorate cisplatin-induced nephrotoxicity.•Organic Cation Transporter 2 has a crucial role in cisplatin-induced nephrotoxicity.•Liraglutide and Rabeprazole have a nephroprotective effect by suppressing the MAPK pathway.•The activation of GLP-1 receptor alleviates cisplatin nephrotoxicity.•The combination of liraglutide and rabeprazole demonstrates the most renoprotective effect.