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

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Abstract

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.

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Acknowledgments

This work was supported by funds from the Sultan Qaboos University. Thanks are due to Professor Gerald Blunden for reading the MS and to the staff of the SQU Small Animal House for looking after the animals.

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman

    Mohammed Al Za’abi, Yousuf Al Suleimani, Mohammed Ashique, Priyadarsini Manoj & Badreldin H. Ali

  2. Department of Pathology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates

    Suhail Al Salam

  3. Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates

    Abderrahim Nemmar

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  1. Mohammed Al Za’abi
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  2. Suhail Al Salam
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Contributions

BHA and MAZ conceived and designed the project. MA and PM conducted the experiments. SAS contributed to histopathology work. YAS and AN contributed to interpretation of data. BHA and MAZ wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Mohammed Al Za’abi.

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Ethical approval

This research was approved by the Animal Research Ethics Committee of the Sultan Qaboos University (SQU/AEC/2019–20/11). Procedures involving animals and their care were carried out in conformity with international laws and policies (EEC Council directives 86/609, OJL 358, 12 December 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publications No. 85–23, 1985).

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Al Za’abi, M., Al Salam, S., Al Suleimani, Y. et al. Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats. Naunyn-Schmiedeberg's Arch Pharmacol 394, 249–259 (2021). https://doi.org/10.1007/s00210-020-01976-1

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