Expression of ER stress markers (GRP78 and PERK) in experimental nephrotoxicity induced by cisplatin and gentamicin: roles of inflammatory response and oxidative stress

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2023-04, Vol.396 (4), p.789-801
• Main Authors: Metin, Tuba Ozcan, Bayrak, Gulsen, Yaman, Selma, Doganer, Adem, Yoldas, Atila, Eser, Nadire, Aykan, Duygun Altintas, Yilmaz, Banu Coskun, Kurt, Akif Hakan, Ayaz, Lokman, Sahin, Mehmet
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cisplatin; Cisplatin - toxicity; Creatinine; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gentamicin; Gentamicins - metabolism; Gentamicins - toxicity; Induction therapy; Inflammation; Inflammation - drug therapy; Kidney; Kidneys; Neurosciences; Oxidants; Oxidative Stress; Pharmacology/Toxicology; Rats; Stress proteins; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-022-02358-5

This study aimed to establish the relationship between two endoplasmic reticulum (ER) stress proteins, glucose-regulated protein 78 (GRP78/BiP) and PKR-like endoplasmic reticulum kinase (PERK), and oxidative stress markers in cisplatin (CIS)–induced and gentamicin (GEN)–induced nephrotoxicity. The study consisted of five groups: control (saline solution only), CIS D2 (2.5 mg/kg for 2 days), CIS D7 (2.5 mg/kg for 7 days), GEN D2 (160 mg/kg for 2 days), and GEN D7 (160 mg/kg for 7 days). All rats were sacrificed 24 h after the last injection for standard clinical chemistry, and ultrastructural and histological evaluation of the kidney. CIS and GEN increased blood urea nitrogen (BUN) and serum creatinine (Cr) levels, as well as total oxidant status (TOS), while decreasing total antioxidant status (TAS) level in CIS D7 and GEN D7 groups. Histopathological and ultrastructural findings were also consistent with renal tubular damage. In addition, expression of markers of renal inflammation (tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β)) and ER stress markers (GRP78 and PERK) was significantly increased in the kidney tissue of rats treated with CIS and GEN for 7 days. These findings suggest that CIS and GEN administration for 7 days aggravates nephrotoxicity through the enhancement of oxidative stress, inflammation, and ER stress–related markers. As a result, the recommended course of action is to utilize CIS and GEN as an immediate but brief induction therapy, stopping after 3 days and switching to other drugs instead.