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Published on: November 8, 2015
Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45α Pathway
Ping Gao1,2, Xinwei Cheng3,4, Rui Xu1
1Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.
Abstract:
Tacrolimus-induced chronic nephrotoxicity (TICN) limits its clinical application without prevention strategies. Identifying a specific target and finding corresponding drug are critical for its prevention. We previously found that transcription factor EB (TFEB), a substrate of calcineurin, is key to TICN. Further exploration of drugs targeting TFEB without compromising tacrolimus efficacy holds promise for preventing TICN. Astragaloside IV (AS-IV), the major bioactive component of Astragali Radix, can alleviate various renal diseases. However, its regulatory effect on TFEB and the underlying mechanism remain unknown. Herein, we found that AS-IV significantly reactivated TFEB and restored tacrolimus-impaired renal function and pathology, autophagy flux and DNA repair. These effects were reversed upon TFEB knockdown. Further studies revealed that AS-IV did not affect calcineurin but activated TFEB by inhibiting mTOR, which dominantly phosphorylated TFEB Ser211. Altogether, this study suggested that AS-IV mitigated TICN via mTOR-TFEB without affecting calcineurin, making it a promising therapeutic agent for TICN.
Insights
Astragaloside IV prevents tacrolimus-induced chronic nephrotoxicity by reactivating transcription factor EB (TFEB) through mTOR inhibition. This approach restores kidney function and pathology without impacting calcineurin activity.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Tacrolimus-induced chronic nephrotoxicity (TICN) is a significant clinical challenge.
- Transcription factor EB (TFEB) is identified as a key factor in TICN.
- Developing preventive strategies targeting TFEB is crucial for safe tacrolimus use.
Purpose of the Study:
- To investigate the effect of Astragaloside IV (AS-IV) on TFEB.
- To elucidate the mechanism by which AS-IV mitigates TICN.
- To evaluate AS-IV as a potential therapeutic agent for TICN.
Main Methods:
- AS-IV treatment in a TICN model.
- TFEB reactivation assessment.
- Analysis of renal function, pathology, autophagy flux, and DNA repair.
- Investigation of the mTOR and calcineurin pathways.
- TFEB knockdown experiments.
Main Results:
- AS-IV reactivated TFEB and improved renal function and pathology in TICN.
- AS-IV restored autophagy flux and DNA repair.
- These beneficial effects were dependent on TFEB.
- AS-IV inhibited mTOR, leading to TFEB activation, without affecting calcineurin.
- AS-IV demonstrated efficacy in mitigating TICN via the mTOR-TFEB pathway.
Conclusions:
- AS-IV effectively mitigates TICN by activating TFEB through mTOR inhibition.
- This mechanism preserves renal function and pathology without compromising calcineurin activity.
- AS-IV shows promise as a preventive therapy for TICN.
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