Efeito protetor de p-Aminofenilchalconas sintéticas em modelo de citotoxicidade induzida por Gentamicina em células tubulares

Abstract

Drug-induced Acute Kidney Injury (AKI) is a serious health problem worldwide, especially in the hospital environment, and can lead the patient to develop chronic kidney disease or even todeath. Antibiotics such as Gentamicin, from the class of aminoglycosides, are widely used inclinical routine despite being known to be nephrotoxic. It is estimated that about 10 to 20% of patients who use it are affected by kidney damage resulting from oxidoreductive imbalance, which causes cell death and acute tubular necrosis. In this context, several natural and synthetic substances with antioxidant properties, such as chalcones – aromatic ketones from the flavonoid family – have been studied as potential nephroprotectors. The present work aimed to evaluate the cytoprotective and antioxidant potential of p-aminoacetophenone-derived chalcones (paminophenylchalcones) in an in vitro model of gentamicin-induced acute kidney injury in renal tubular cells. For this, the cultivation of HK-2 cells, human renal tubular cells, which were treated with gentamicin sulfate at different concentrations (8.0; 4.0; 2.0; 1.0; 0.5 mM) to define the IC50 (5,28 ± 0,57 mM). Then, the pre- and post-treatment procedures with paminophenylchalcones with concentrations of 125-7,81 μM were evaluated. The evaluation of cytotoxicity and cell viability after treatment was performed using the MTT reduction assay. The oxidant character of gentamicin-induced injury was evaluated by determining the accumulation of superoxide anions (O2 −,) and the levels of reduced glutathione (GSH) in HK-2 cells. Aminochalcones with an increase in the central carbon chain and the presence of a fluorine atom in its structure were toxic to kidney cells at all concentrations tested. Only paminophenylchalcones containing -NO2 (nitro) and -N(CH3)2 (dimethyl amino) groups attached to the B ring at the C-4 position showed a protective effect after injury induced by Gentamicin. The treatment with the aminoglycoside reduced the cellular stock of GSH and led to a greater accumulation of O2 − , effects partially reversed through post-treatment with the paminophenylchalcones at concentrations of 31.25-7.81 µM. Furthermore, it was observed that nitro substituted p-aminophenylchalcone was able to recover cell viability by up to 11% after damage induced by Gentamicin. Thus, the present study highlights p-aminophenylchalcones as potential new antioxidant pharmacological tools and contributes to the development of scientific knowledge for modeling future new drugs for AKI therapy.