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.

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.