Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 394; no. 2; pp. 249 - 259
• Main Authors: Al Za’abi, Mohammed, Al Salam, Suhail, Al Suleimani, Yousuf, Ashique, Mohammed, Manoj, Priyadarsini, Nemmar, Abderrahim, Ali, Badreldin H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2021; Springer Nature B.V
• Subjects: Actin; Acute Kidney Injury - chemically induced; Acute Kidney Injury - complications; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Albuminuria - blood; Albuminuria - chemically induced; Albuminuria - pathology; Albuminuria - urine; Animal models; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biomedical and Life Sciences; Biomedicine; Caspase 3; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Collagen (type I); Creatinine - blood; Creatinine - metabolism; Creatinine - urine; Cytokines; Disease Models, Animal; Dose dependency; Dose-Response Relationship, Drug; Fatty Acid-Binding Proteins - metabolism; Fibrosis; Indican - blood; Inflammation; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney diseases; Male; Neurosciences; NF-E2-Related Factor 2 - metabolism; Original Article; Pharmacology/Toxicology; Phosphorus - blood; Rats; Rats, Wistar; Renal Insufficiency, Chronic - chemically induced; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Urea - blood; Uric Acid - blood; Animal models; Chronic kidney disease; Acute kidney injury; Cisplatin; Fibrosis
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-020-01976-1

Cisplatin (CP) is nephrotoxic, and this side effect is used as an animal model for acute kidney injury (AKI). Earlier research has been focused on CP-induced AKI, with relatively little attention being paid to its ability to progress to chronic kidney disease (CKD) on repeated administration. We aimed here to test the dose dependency of its nephrotoxic actions by comparing various physiological, biochemical, molecular, and histopathological indices using repeated increasing doses of CP in rats. Furthermore, we investigated whether these doses of CP would result in the development of CKD. Biochemical, molecular, and histopathological measurements were conducted in plasma, urine, and/or kidneys of rats treated with increasing doses of CP at 1.6, 3.2, and 4.8 mg kg −1 weekly for four consecutive weeks. These doses induced significant and dose-dependent elevations in most of the measured renal indices. These included increased renal fibrosis, as suggested histopathologically and biochemically by the significant increase in transforming growth factor-β1, significant decrease in actin alpha 2, and variable actions of collagen I and IV. CP also dose-dependently increased nuclear factor (erythroid-derived 2)-like 2 and caspase-3. Multiple repeated doses of CP (1.6 to 4.8 mg kg −1 ) induced multiple episodes of AKI, leading to CKD after the 4th weekly dose and confirmed that this dosage regimen could be used as an experimental animal model of AKI progressing to CKD. These actions were driven by inflammation, oxidative, and nitrosative stress.