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Published on: March 20, 2018
Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced
Gerui Zhu1, Fan Wang2, Siyuan Wang2
1Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine，Shanghai 201203, China; Shanghai Academy of Internationl Standardization for Traditional Chinese Medicine,Shanghai 201203,China.
Abstract:
Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.
Insights
Aristolochic acid I (AAI) causes liver and kidney damage by activating STAT3. Inhibiting STAT3 with Stattic protected cells, revealing STAT3 as a key target in AAI-induced hepatorenal toxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Hepatology and Nephrology
Background:
- Aristolochic acids (AAI) are known nephrotoxins and carcinogens.
- Previous research indicates AAI induces hepatorenal toxicity, but mechanisms are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Aristolochic acid I (AAI)-induced hepatorenal toxicity.
- To identify common molecular targets of AAI in liver and kidney damage.
Main Methods:
- In vivo studies using C57BL/6 mice and in vitro studies with human hepatocytes (HL-7702/L-02) and kidney tubular cells (HK-2).
- RNA sequencing of liver and kidney tissues to identify toxicity mechanisms.
- Validation experiments using STAT3 inhibitor (Stattic).
Main Results:
- AAI exposure led to impaired liver and kidney function and tissue damage in mice and cell lines.
- RNA sequencing identified STAT3 as a common target, with AAI increasing STAT3 phosphorylation.
- STAT3 inhibition significantly reduced AAI-induced cellular damage.
Conclusions:
- STAT3 is a critical mediator of Aristolochic acid I-induced hepatorenal toxicity.
- Targeting STAT3 may offer a therapeutic strategy against AAI-induced liver and kidney damage.
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