Glimepiride ameliorates renal toxicity induced by cadmium in mice: Modulation of Jun N terminal kinase (JNK)/nuclear factor kappa B (NF-κB) and phosphatidylinositol 3-kinases (PI3K)/protein kinase (AKT) pathways

Abstract

AimsNephrotoxicity is one of the most serious health consequences of cadmium (Cd) toxic exposure. Cd was associated with nephrotoxicity through different mechanisms including apoptosis, inflammation, and oxidative stress. This study investigated the effects of glimepiride on renal inflammatory reactions and oxidative stress in response to Cd in mice animal model, pointing to the possible role of JNK/NF-кB and PI3K/AKT signaling. Materials and methodsFour groups of animals were created; the control group, the glimepiride group (4 mg/kg; i.p.), CdCl2 nephrotoxic group (6.5 mg/kg; i.p.), and the CdCl2/glimepiride group. On the other hand, molecular docking studies were used to investigate the affinity of glimepiride towards JNK, AKT, and PI3K targets. Key findingsThe CdCl2 group's serum creatinine and urea levels were found to have a significant increase when compared to the normal group. High expression of 8-OHDG, JNK, AKT, and NGAL was also detected in the CdCl2 group. In addition, coagulative necrosis of the renal tubules and increased immunostaining of NF-κB and PI3K. Furthermore, glimepiride significantly decreased the serum creatinine and urea level and alleviated the degenerative and necrotic changes within the renal tubules. Moreover, the renal NGAL and JNK were suppressed, and oxidants/antioxidants hemostasis was observed. SignificanceThe available data show that glimepiride is an attractive strategy for improving the nephrotoxicity associated with CdCl2 through inhibition of JNK/NF-κB, PI3K/AKT inflammatory pathways. From the abovementioned results, glimepiride treatment might be a potential therapeutic approach to treat renal tissue against severe acute renal damage induced by the toxic effects of CdCl2.