# Evaluation of Ototoxic Effects of Cisplatin in a Rat Model: A Dose-Response Study
## 4 Discussion
CDDP was mainly excreted through glomerular filtration and tubular secretion, with a smaller amount being excreted through tubular secretion [35]: within the first 24 h after administering cisplatin, more than 50% of the drug was excreted in the urine and the concentration achieved in the kidney cortex is several times higher than that in plasma and other organs, which explains the high incidence of nephrotoxicity [17; 65; 66; 67]. The proximal tubular cells, and especially segment S3, were specifically damaged by the direct cytotoxic effects of CCDP. Histopathology suggests that tubular-interstitial lesions were caused by necrosis and apoptosis, particularly in cells that have more proliferative activity [68; 69]. In vivo studies have revealed atrophy of the glomeruli and damage to the renal tubules, leading to the formation of hyaline casts and areasof tubular necrosis [70; 71]. In vivo studies on CDDP nephrotoxicity in rats have been carried out using various protocols, with 7.5 mg/kg IP injected as a single dose, to cumulative doses of 15 mg/kg (three IP doses of 5 mg/kg) [30; 33; 70]. In our investigation, a dose of 14 mg/kg led to atrophy of the renal glomeruli, with a decrease in their area of approximately 17%, without significant differences between the treatment groups. Despite this, both treatment methods showed significant alterations in tubular damage compared to control. In general, both PCTs and DCTs were affected, with epithelial dilation, detachment, and necrosis of PT cells. These findings were consistent with the results previously reported in studies that examined nephrotoxicity in mice and rats that received a lower dose of cisplatin [72; 73; 74]. Furthermore, we identified inflammatory cells in necrotic areas and hyaline urinary casts (mainly in DCTs), which agrees with the findings of previous studies [30; 40; 70; 71]. Both the 1-IP and 3-IP groups showed damage throughout their cortical regions, accompanied by extensive infiltration of inflammatory cells and hyaline urinary casts, indicating a decrease in diuresis and solute concentration during DCT. The boundary zone between the cortical and medullary regions was the area most affected by CDDP, and it appeared that CDDP accumulates there first, as demonstrated in rat models [75; 76]. The physiological mechanisms have not been fully explained, but the hypothesis is that basolateral drug transporters and organic cation transporters play a role in it [77; 78; 79; 80; 81]. CDDP nephrotoxicity has been suggested to be caused by inflammation and oxidative stress [17; 70]. The inflammatory response caused by CDDP administration can cause or worsen AKI by producing TNF-\(\alpha\) and other cytokines in epithelial cells themselves, eventually leading to activation of NF-kB and iNOS, resulting in the release of NO and peroxynitrite and leading to damage caused by oxidative stress. CDDP targets mitochondria, and they play a greater role in mediating chemotherapy-induced cell death than DNA damage [82]. Cell sensitivity to CDDP was related to the number of mitochondria [83]. This could explain why CDDP had a negative impact on PCT epithelial cells in the kidney, stria vascularis, spiral ligament, organ of Corti, and spiral ganglion neurons in the cochlea, as cells in these tissues were reported to be rich in mitochondria, making them highly sensitive to oxidative stress [84; 85]. Although the mechanism behind CDDP cellular toxicity has been extensively studied, it is still incompletely understood. The presence of oxidative stress could have a significant impact, with decreased levels of endogenous antioxidant enzymes (such as SOD, catalase, glutathione peroxidase, and glutathione reductase) and higher levels of stimulating enzymes, such as NADPH oxidase, which could increase lipid peroxidation and accumulate ROS and reactive nitrogen species (RNS) in tissues [30; 33; 39; 63; 64; 70; 71; 86]. When ROS and RNS interact, peroxynitrite (ONOO-) is formed, which is a nitrogen radical that nitrates protein tyrosine.