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Published on: July 17, 2016
Role of MARK4 in methamphetamine-induced acute kidney injury
Jin Tang1, Guoqian Hu2, Liang Zeng2
1Department of Urology, Third Xiangya Hospital, Central South University, Changsha 410013. ajin530@139.com.
Objectives:
Methamphetamine (METH) is an illicit psychoactive substance that can damage various organs, with the urinary system being one of its significant targets. This study aims to explore the role of microtubule affinity-regulating kinase 4 (MARK4) in METH-induced acute kidney injury (AKI).
Methods:
A total of 10 healthy adult male C57BL/6 mice were randomly divided into a control group and a METH group, 5 mice in each group. The METH group was administered METH (20 mg/kg, intraperitoneally, once daily for 3 consecutive days), while the control group received an equal volume of physiological saline. The mice were executed 24 hours after the final injection, and the success of the AKI model was detected by blood serum creatinine, blood urea nitrogen, and renal HE staining. Proteins differentially expressed between kidney tissues with METH-induced AKI and normal kidney tissues were screened by proteomics techniques and subjected to gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and bioinformatics analysis. The accuracy of proteomic data was validated using Western blotting, and the expression levels of MARK4 and cleaved caspase-3 in mouse kidneys were measured. We further explored the role of MARK4 in METH-induced AKI. Firstly, a METH toxicity model was established in BUMPT cells to screen the appropriate concentration and time of METH treatment; the viability of BUMPT cells after METH treatment and the expression of cleaved caspase-3 were detected by interfering with MARK4 expression through inhibitors.
Results:
The proteomic analysis of kidney tissues from METH and control groups screened for a total of 17 differentially expressed proteins, of which 11 were up-regulated and 6 were down-regulated (all P<0.05). The expression levels of MARK4 and cleaved caspase-3 were elevated in the kidneys of METH-treated mice (both P<0.05). The activity of BUMPT cells gradually decreased with increasing METH treatment concentration (all P<0.05), where the viability of BUMPT cells decreased to about 60% after METH treatment at 4 mmol/L. Compared with the control group, expression levels of MARK4 and cleaved caspase-3 were increased with higher METH concentrations and longer exposure times in a concentration- and time-dependent manner (all P<0.05). Inhibition of MARK4 expression improved METH-induced decrease in BUMPT cell activity, down-regulated the expression of cleaved caspase-3, and decreased the apoptosis of BUMPT cells induced by METH.
Conclusions:
MARK4 is highly expressed in a mouse model of METH-induced AKI, and MARK4 mediates METH-induced AKI by regulating cell apoptosis.
Insights
Methamphetamine (METH) causes acute kidney injury (AKI) by increasing microtubule affinity-regulating kinase 4 (MARK4) expression. Inhibiting MARK4 reduces METH-induced AKI and cell apoptosis.
Area of Science:
- Nephrology
- Molecular Biology
- Toxicology
Background:
- Methamphetamine (METH) is a potent illicit drug known to cause multi-organ damage, particularly affecting the urinary system.
- Acute kidney injury (AKI) is a significant clinical concern associated with METH abuse.
- Microtubule affinity-regulating kinase 4 (MARK4) has emerged as a potential factor in cellular stress responses.
Purpose of the Study:
- To investigate the role of MARK4 in the pathogenesis of METH-induced AKI.
- To elucidate the molecular mechanisms underlying METH-induced kidney damage.
- To assess the therapeutic potential of targeting MARK4 in METH-induced AKI.
Main Methods:
- Establishment of a METH-induced AKI mouse model and a METH toxicity cell model (BUMPT cells).
- Proteomic analysis to identify differentially expressed proteins in kidney tissues.
- Validation of protein expression using Western blotting.
- In vitro experiments involving MARK4 inhibition in METH-treated cells.
Main Results:
- Proteomic analysis revealed 17 differentially expressed proteins in METH-induced AKI kidney tissues.
- MARK4 and cleaved caspase-3 expression were significantly elevated in METH-treated mice kidneys.
- MARK4 inhibition attenuated METH-induced BUMPT cell damage, reduced cleaved caspase-3 expression, and decreased apoptosis.
Conclusions:
- MARK4 is upregulated in METH-induced AKI.
- MARK4 plays a crucial role in mediating METH-induced AKI by regulating cell apoptosis.
- Targeting MARK4 presents a potential therapeutic strategy for METH-induced kidney injury.
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