5-FU is a widely used chemotherapeutic in chemotherapy and causes multiple organ toxicities. The protective or therapeutic effects of flavonoids in organ toxicity models caused by anticancer agents have been reported in many studies. In our study, the protective effects of Quercetin in 5-FU-induced nephrotoxicity in rats were investigated.
Urea, creatinine and BUN levels are measured routinely in the evaluation of kidney functions in the clinic. As a result of many studies, increases in blood urea, creatinine and BUN levels are shown as evidence of renal dysfunction 17-18. In experimentally generated nephrotoxicity models, renal function tests are routinely evaluated. The therapeutic or protective effects of some agents on kidney functions impaired by toxic compounds or chemicals have been investigated in many studies 19,20. Atessahin et al. 21 stated that rats treated with cisplatin experienced a decrease in glomerular filtration rate and an increase in serum urea and creatinine levels. Gelen et al. 5 determined that serum creatinine and BUN levels increased significantly in the nephrotoxicity model induced by 5-FU in rats and that the application of Naringin for protective purposes inhibited the increase in these parameters. In another study, it was determined that Quercetin administration prevented the increase in urea and creatine levels in cisplatin-induced acute nephrotoxicity model in rats 22. In our study, it was observed that urea, creatinine and BUN levels increased significantly in serum samples obtained 48 hours after 5-FU application compared to control in the 5-FU group and especially the high dose of Quercetin has a protective effect against 5-FU nephrotoxicity. It is thought that this effect of Quercetin prevents kidney damage caused by 5-FU and accordingly the increase in these parameters.
GSH, SOD and GPx are among the best-known antioxidants in tissues. GPx, enzyme-containing selenium in the GSH active region, reacts with hydrogen peroxide (H2O2) and organic peroxides, and removes H2O2 from the cell, and shows an antioxidant effect 23,24. Reactive oxygen species stimulate lipid peroxidation (LPO) by acting on fatty acids in the cell membrane. The best known of the aldehydes released by lipid peroxidation is MDA. Many studies have reported that anticancer agents stimulate oxidative stress in cells, decrease SOD and GPx activities and increase MDA levels 7,16. Gelen et al. 5 determined that 5-FU administration causes hepatotoxicity and nephrotoxicity in rats, and 5-FU induces renal oxidative stress and causes a significant increase in MDA level and a decrease in SOD and GSH activities. Researchers reported that Quercetin prevents lipid peroxidation and oxidative stress in lung 6, liver 16,25, and renal 25 toxicity induced by anticancer agents in rats. In accordance with the literature, our study revealed that 5-FU induced renal oxidative stress in rats, increased kidney MDA levels, and significantly decreased SOD and GPx activities. It was determined that Quercetin prevents oxidative stress caused by 5-FU with its strong antioxidant activity.
IL-33, a proinflammatory cytokine, is released from necrotic cells and binds to STR2R receptors on immune cells 26. It increases the secretion of cytokines following its binding to related receptors, and inflammation is stimulated due to these events 27. IL-33 stimulates CD4 T cell infiltration in the kidneys, resulting in kidney damage. It was determined that the levels of IL-33 increased in the model of acute kidney injury induced by cisplatin and IL-33 was predominantly expressed in the glomeruli, blood vessels, and peritubular capillaries in the kidneys 28. Sengul et al. 17 reported that renal IL-33 levels significantly increased in acrylamide-induced nephrotoxicity in rats. Our findings were consistent with the literature, and it was determined that 5-FU administration significantly increased renal IL-33 levels, and Quercetin administration for protective purposes prevented the increase in IL-33 levels.
Kidneys are the most important organs where AQPs, known as specific water channels, are expressed in the organism. AQP-1 is the most expressed among the aquaporins defined in the kidney (AQP-1, AQP-2, AQP-3, AQP-4) and AQ1, especially in the proximal tubule where water resorption is most common, and in the thin descending arm of henella (29,30). Lajer et al. 31 reported that renal AQP-1 expression decreased statistically significantly in cisplatin-induced nephrotoxicity. Kucukler et al. 32 determined that AQP-1 levels were decreased in lead acetate-induced nephrotoxicity in rats and the administration of Chrysin, a flavonoid, prevented this decrease. In a another study, AQP-1 expression decreased significantly in the medulla and did not change in the cortex of cisplatin-administered rats 33. Contrary to the literature, according to the findings obtained from our study, it was determined that there was no difference between the experimental groups in the expression of renal AQP-1 in rats that we applied 5-FU and Quercetin.
The nephrin is a protein structure that is synthesized by podocytes in glomeruli, encoded by the Nephrotic Syndrome Type 1 gene, protecting the viability of podocytes, the structure of glomerulus, and functions in the kidneys of adults 34. Gu et al. 35 reported that nephrotoxicity induced by doxorubicin in rats significantly decreased expression of the nephrin compared to healthy rats. In the study conducted by Na et al. 36, in adriamycin-induced nephropathy in rats, the expression of the nephrin decreased significantly in the group treated with adriamycin compared to the control group. According to the findings obtained in our study, it was found that the levels of the nephrin decreased in the toxicity group compared to the control group in the 5-FU-induced nephrotoxicity model. However, it was not statistically significant as stated in the literature. It was determined that Quercetin administration did not cause a change in renal nephrin levels.
In the models of nephrotoxicity induced by anticancer agents, some pathologies occur in the histological structure of the kidney tissue. It has been reported that the administration of 5-FU, which is widely used in chemotherapy, causes kidney tissue damage, degeneration and necrosis in tubular epithelial cells 37. Gelen et al. 5 reported to tubular dilatation, glomerular atrophy, Bowman's capsule dilatation, degeneration and necrosis in renal tubular epithelial cells in the histopathological evaluation of kidney tissues of rats administered 5-FU. Also, they have found that the application of Naringin, an antioxidant and anti-inflammatory flavonoid, prevented the formation of renal pathologies by providing a protective effect. In our study, it was determined that the histopathological findings of the kidney tissues of the rats in the experimental groups were compatible with the literature and there was shrinkage in the glomerulus, degeneration in the renal corpuscles and dilatation in the Bowman capsule in the 5-FU group. In addition, the presence of swelling, vacuolization, hypertrophic changes and desquamation areas in the tubular epithelium was determined. Intense connective tissue increase and dilatation of the vessels were among the findings obtained around Bowman capsules and in the intertubular areas. It was determined that the low dose of Quercetin prevented these pathologies at a moderate level, and the high dose prevented pathologies in the kidney tissue by providing a significant protective effect, reducing the dilatation in the Bowman capsules, reducing the degeneration in the tubular epithelium and there was no connective tissue increase.
In conclusion, in this study, we determined that 5-FU causes renal dysfunction by increasing oxidative stress in rat kidney tissue, deactivating the antioxidant defense system and causing inflammation and Quercetin administration protected against side effects of 5-FU in kidney tissue of rats.
Acknowledgment
We thank Assoc. Prof. Semin GEDİKLİ for histopathological results and support.
)
)
)
)
