Evaluation of the protective effect of dapagliflozin in preventing vancomycin- induced nephrotoxicity in rats

Purpose: Drugs are an important cause of nosocomial kidney injury. Antibiotics are one of the drug groups that frequently cause nephrotoxicity. SGLT-2 inhibitors have the potential to improve renal function by reducing renal inflammation, oxidative stress and apoptosis. We aimed to evaluate the protective effect of dapagliflozin in vancomycin-induced nephrotoxicity in rats by performing biochemical and histopathologic analyses. Material- Method: This study was conducted using 28 male Wistar-Albino rats after approval of Çukurova University Animal Experiments Local Ethics Committee. The rats were randomly divided into four groups. Groups: 1. Control group (isotonic 15 mg/kg/day intraperitoenal), 2. Dapagliflozin group (10 mg/kg/day oral gavage), 3. Vancomycin group (2x200 mg/kg/day intraperitoenal) and 4. Vancomycin + Dapagliflozin group (dapagliflozin 10 mg/kg oral gavage and vancomycin 2x200 mg/kg/day intraperitoenal) drugs were administered for seven days. At the end of the study period, intracardiac blood samples were taken and nephrectomy was performed. Biochemical parameters were examined to evaluate renal damage between the groups. Hematoxilen-eosin and Periodic Acid-Schiff staining were performed for renal tissue pathological evaluations. To demonstrate inflammation, TNF-α, IL-1β and IL-6 expression in kidney tissue was examined by immunohistochemical method. Statistical analyses were performed in SPSS 27.0 package program and p0.05). Findings: There was a significant difference between the groups in blood urea azatu (p<0.001), creatinine (p<0.001), total anti-oxidant (p=0.014), superoxide dismutase (p=0.004), malondialdehyde (p=0.016) and caspase-3 (p=0.026) levels. No significant difference was found between glutathione peroxidase, catalase, total oxidant capacity, oxidative stress index, myeloperoxidase, Bax and Bcl-2 levels (p>0.05). Kidney weight values (p<0.001) of rats in the Vancomycin group were higher than those in the Control, Dapagliflozin and Vancomycin+Dapagliflozin groups. There was a significant difference between the groups in length (length, width and thickness) (p<0.001) parameters. In renal histopathological evaluation, tubular dilatation (p<0,001), tubular vacuolization (p<0,001), hyaline cilia (p<0,001), tubular necrosis (p<0,001), tubular atrophy (p<0,001) were found in the kidneys of rats in the Vancomycin group, tubular inflammation (p<0.001), interstitial edema (p<0.001), mononuclear cells in the medulla (p<0.001), medullary hemorrhage (p<0.001), necrotic area in the cortex (p<0.001) and tubular desquamation (p<0.001); were found to be higher than the rats in the control, Dapagliflozin and Vancomycin+Dapagliflozin groups. In renal immunohistochemical evaluation, there was a significant difference between the groups in TNF-𝛼 (p<0.001), IL-1β (p<0.001) and IL-6 (p<0.001) expression levels. Conclusion: In our study, we found that serum creatinine, blood urea nitrogen and histopathological damage signs in vancomycin-induced nephrotoxicity in rats were decreased by dapagliflozin. We found that dapagliflozin showed anti-inflammatory properties in this protective effect; however, further studies are needed to understand its effects on oxidative stress and apoptosis. Dapagliflozin may be an effective treatment option for the prevention of vancomycin-associated nephrotoxicity. Keywords: Dapagliflozin, Vancomycin-Associated Nephrotoxicity, Rat, SGLT-2 Inhibitors, Acute Kidney Injury