Molecular Mechanism Of Acute Kidney Injury By Remdesivir (Study on Hypoxic Animal Model Coprecipitated with Diabetes)
Remdesivir is 49% excreted through glomerular filtration and 10% by tubular secretion, thus increasing the risk of nephrotoxicity, but its molecular toxicity mechanism is not yet known. This study aimed to determine the molecular mechanism of remdesivir nephrotoxicity in diabetic rats. Forty healthy male Wistar (Han) rats aged 8-9 weeks, weighing 150-200 grams, were randomly assigned to a normal and a diabetic group. The diabetic group was induced by streptozotocin 65 mg/kg single dose intraperitoneally, and the diabetic state was considered if the random blood glucose level was > 250 mg/dl or fasting blood glucose > 150 mg/dl. Each group was further divided into five, namely the control group that received water for injection, and the test group that was given remdesivir injection through the tail vein at a single dose of 10 mg/kg or the 28-day sub-chronic dose of 3, 6.5, 10 mg/kg/day. The results showed that remdesivir caused a decrease in estimated glomerular filtration rate (eGFR), which was not significant (p>0.05), and acute kidney injury (AKI) based on histopathological analysis, but no fibrosis was found on Masson trichome (MT) staining. There was a statistically significant difference in expression of tubular impairment markers KIM-1 (p <0.0001) and NGAL (p<0.001). All groups had a statistically significant difference in the PIM’s H-score (p<0.0001). The upregulated gene expression was IL-18 (p<0.0001), HIF-1α (p<0.001), and HIF-2α (p<0.001). It can be concluded that the molecular mechanism of remdesivir-induced AKI in diabetic rats is activation of the HIFs through the IL-18 pathway. This study suggested elaborating on other pathways.
Keywords: COVID-19, remdesivir, hypoxia, diabetes, molecular mechanism
