ORIGINAL ARTICLE Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats Mohammed Al Za’abi 1 & Suhail Al Salam 2 & Yousuf Al Suleimani 1 & Mohammed Ashique 1 & Priyadarsini Manoj 1 & Abderrahim Nemmar 3 & Badreldin H. Ali 1 Received: 12 August 2020 /Accepted: 7 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 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 histopatho- logical 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. Keywords Acute kidney injury . Animal models . Chronic kidney disease . Cisplatin . Fibrosis Introduction Cisplatin (CP) is a potent inorganic platinum-based antineo- plastic drug that is commonly used in the treatment of several types of cancers that include otherwise resistant solid tumors, e.g., lymphomas, stomach, esophagus, pancreas, bladder, head and neck, lung, ovaries, and testes cancers (Szturz et al. 2019; Ojima et al. 2019). CP-based chemotherapy in cancer patients causes sev- eral adverse effects. Usage of CP is hampered by nephro- toxicity, as it has been reported that about 25–40% of the cancer patients treated with it show a progressive reduc- tion in renal function, even in the absence of other factors such as advanced age and preexisting renal conditions (Sharp et al. 2016). More than 70% of children given a single dose of CP experience renal dysfunction (Karasawa and Steyger 2015; Hoek et al. 2016). AKI can progress to chronic kidney disease (CKD), and CKD, conversely, pre- disposes to AKI, indicating that these two conditions are interconnected (He et al. 2017). CP nephrotoxicity is known to be the dose-limiting adverse effect that can lead to acute kidney injury (AKI), followed by chronic renal problems (Latcha et al. 2016; Sharp et al. 2018). AKI and CKD are both serious global public health problems (Anand et al. 2019; He et al. 2017; Uber and Sutherland 2019). In the USA, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01976-1) contains supplementary material, which is available to authorized users. * Mohammed Al Za’abi zaabi@squ.edu.om 1 Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman 2 Department of Pathology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates 3 Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates Naunyn-Schmiedeberg's Archives of Pharmacology https://doi.org/10.1007/s00210-020-01976-1