AUTHOR=Liu Fang , Liu Yan , Peng Qifeng , Wang Guodong , Tan Qing , Ou Zhongyue , Xu Qishan , Liu Chixiang , Zuo Daming , Zhao Jianbo 

TITLE=Creatinine accelerates APAP-induced liver damage by increasing oxidative stress through ROS/JNK signaling pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.959497

DOI=10.3389/fphar.2022.959497

ISSN=1663-9812

ABSTRACT=Serum creatinine is an endogenous biomarker to estimate glomerular filtration rate and is commonly used to assess renal function in clinical practice. Acetaminophen (APAP), the most available analgesic and antipyretic medication, is recommended as the drug of choice for pain control in patients with renal diseases. However, an overdose of APAP can lead to severe acute liver injury, which is also the most common cause of acute liver failure in western countries. Herein, we analyzed clinical data on patients with drug-induced liver injury accompanying with increased creatinine. The results revealed that the creatinine concentration between 82-442μmol/L for female and 98-442μmol/L for male is positively correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST). While there was no correlation between creatinine and ALT and AST when creatinine concentrations is over 442μmol/L. In addition, mice were administrated with creatinine intraperitoneally for one week before APAP injection to investigated the pathophysiological role of creatinine in APAP-induced acute liver injury. The data showed that creatinine administration aggravated hepatic necrosis and elevated serum lactate dehydrogenase (LDH) and ALT levels in mice upon APAP injection. We also demonstrated that creatinine could increase the production of reactive oxygen activation (ROS) and the activation of c-Jun N-terminal kinase (JNK). Furthermore, the liver injury was alleviated, and the difference between APAP-treated mice and APAP combined with creatinine-treated mice was disappeared after using specific ROS and JNK inhibitors. Significantly, creatinine stimulation aggravates APAP-induced cell death in HepaRG cells with the same mechanism. In summary, we propose that creatinine exacerbates APAP-induced hepatocyte death by promoting ROS production and JNK activation, thus providing new insight into the usage of APAP in patients with kidney problems.