SIRT6 regulates the HIPK2/P53 pathway to reduce oxidative stress and apoptosis to attenuate vancomycin-induced nephrotoxicity

Abstract

SIRT6 is known to play a protective role in several kidney diseases; however, its role in vancomycin-induced renal injury remains unclear. This study aims to confirm the role and related mechanisms of SIRT6 in vancomycin-induced renal injury. To develop a kidney damage model, mice were given vancomycin injections for seven days. Additionally, an in vivo transfection with a SIRT6 overexpression plasmid was performed. PCR and Western blot analyses were used to assess the SIRT6 mRNA and protein expression levels in renal tissue. HE staining was performed to evaluate renal tissue damage, while Scr and BUN were measured using specialized kits. Renal tissue apoptotic cells were labeled using a TUNEL kit, and the levels of the antioxidant enzymes SOD and GSH were measured using appropriate kits. Western blot was used to identify HIPK2, p-p53, and p53 protein expression in the renal tissue. The results reveal that SIRT6 is expressed at markedly low levels in renal tissue. Furthermore, mice administered vancomycin exhibited a significant increase in Scr and BUN levels, indicating impaired renal function. Histological examination through HE staining demonstrated considerable damage to the renal tissue of the vancomycin group. Additionally, the renal tissue of the mice in the vancomycin group displayed reduced levels of the antioxidant enzymes SOD and GSH, an increased number of TUNEL-positive cells, and significantly elevated levels of HIPK2 and p-p53 protein expression. Moreover, the mice transfected with SIRT6 exhibited significant improvements in previously described symptoms. These findings imply that the inhibition of HIPK2/p53 by SIRT6 may represent a promising therapeutic strategy for alleviating vancomycin-induced nephrotoxicity.