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Activation of the mTOR dependent signaling pathway underlies ketamine-induced uropathy

Chih-Chieh Lin1,2,3, An-Hang Yang1,4,5, Alex Tong-Long Lin1,2,3

  • 1Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Neurourology and Urodynamics
|February 22, 2017
PubMed
Abstract

Insights

Ketamine activates the mammalian target of rapamycin (mTOR) pathway, leading to microvascular injury in the bladder. This pathway activation promotes endothelial-mesenchymal transition, contributing to ketamine-induced cystitis.

Area of Science:

  • Urology
  • Molecular Biology
  • Pathology

Background:

  • Ketamine abuse can cause severe bladder damage, known as ketamine-induced cystitis (KC).
  • The underlying mechanisms of KC, particularly microvascular injury, are not fully understood.
  • The mammalian target of rapamycin (mTOR) pathway plays a role in cellular processes relevant to tissue injury and repair.

Purpose of the Study:

  • To investigate the role of mammalian target of rapamycin (mTOR) pathway activation in ketamine-induced microvascular injury.
  • To explore the potential of targeting the mTOR pathway for therapeutic interventions in KC.

Main Methods:

  • Compared bladder tissue from 23 KC patients and 16 controls.
  • Analyzed phospho-S6 ribosomal protein (p-S6RP), an mTOR pathway marker, in bladder tissues.
  • Investigated in vitro mTOR activation and endothelial-mesenchymal transition (EndMT) in human bladder microvascular endothelial cells (HBdMECs) exposed to ketamine.

Main Results:

  • Ketamine exposure significantly increased p-S6RP expression in KC patients' bladder microvessels.
  • In vitro, ketamine activated the mTOR pathway in HBdMECs, increasing phosphorylated mTOR, S6RP, and p70S6K.
  • Ketamine induced EndMT in HBdMECs, evidenced by CD31 and FSP-1 co-expression, with TGF-β1 involvement.
  • The mTOR inhibitor rapamycin reduced ketamine-induced FSP-1 expression.

Conclusions:

  • Ketamine activates the mTOR pathway in bladder microvascular endothelial cells.
  • This activation leads to mesenchymal phenotypic changes (FSP1 expression) and contributes to endothelial-mesenchymal transition.
  • The findings suggest the mTOR pathway is a key player in ketamine-induced bladder microvascular injury.
Keywords:
endothelial cellendothelial mesenchymal transitionketaminemTOR pathwaymicrovascular injury

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