Advanced oxidation protein products accelerates paracetamol-induced liver injury through AMPK-mTOR signaling pathway in chronic kidney disease

Objectives: Chronic kidney disease (CKD) is a progressive medical condition marked by a gradual decline in kidney function, leading to an accumulation of waste products and fluids in the body. Drug-induced liver injury (DILI) poses a significant clinical challenge in CKD management, with paracetamol being a commonly used medication. Advanced oxidation protein products (AOPPs) are biomarkers of CKD progression and contributors to DILI. However, the mechanisms behind the increased incidence of DILI in CKD remain unclear.

Methods: We developed an adenine-induced CKD mice model, a paracetamol-induced DILI mice model, and an AOPPs-loaded mice model using intraperitoneal injections.

Key findings: Declining renal function in the CKD model was associated with a significant weight loss and increased the concentration of serum creatinine and blood urea nitrogen. Following paracetamol administration, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and N-acetyl-p-benzoquinoneimine and liver tissue necrosis increased significantly in CKD groups. In addition, the expression of Cytochrome P450 2E1 (CYP2E1) and thrombospondin receptor (CD36) were upregulated, while the adenylate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway showed significant changes in protein expression and phosphorylation. In AOPPs-loaded model, AOPPs upregulated AMPK and Akt protein expression, along with reduced mTOR levels. In HepG2 and L0-2 cell lines, AOPPs and paracetamol significantly increased the protein expression and phosphorylation of AMPK and Akt, alongside a decreased mTOR expression and phosphorylation. AOPPs and paracetamol significantly induced the Apoptosis in HepG2 and L0-2 cells. Notably, the expression of CYP2E1 induced by AOPPs and paracetamol was inhibited by dorsomorphin and corynoxine B.

Conclusions: These findings suggest that the AMPK-mTOR signaling pathway mediates the worsening of paracetamol-induced liver injury in CKD, with AOPPs potentially serving as key endogenous factors. This study lays the groundwork for identifying crucial molecules involved in exacerbated paracetamol-induced liver injury in CKD, which may serve as new drug targets and improve the safety profile of paracetamol in patients with CKD.

AMPK; AOPPs; CKD; DILI; mTOR; paracetamol.