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Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney

Rei Unno1, Tsuyoshi Kawabata2, Kazumi Taguchi1

  • 1Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.

Autophagy
|July 2, 2019
PubMed

Insights

Kidney stone formation involves decreased autophagy in renal tubular cells due to mTOR activation. Inhibiting mTOR may offer a new treatment strategy for kidney stones by restoring autophagy and reducing inflammation.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Medicine

Background:

  • Kidney stone disease is a prevalent lifestyle-related condition with limited effective treatments.
  • Cellular damage in renal tubular cells (RTCs) is a key factor in kidney stone development.
  • The role of autophagy in RTCs during kidney stone formation requires further investigation.

Purpose of the Study:

  • To investigate the role of macroautophagy/autophagy in renal tubular cells during kidney stone formation.
  • To identify the molecular mechanisms underlying autophagy impairment in kidney stone disease.
  • To explore the therapeutic potential of targeting autophagy for kidney stone treatment.

Main Methods:

  • Assessed autophagic activity in mouse RTCs exposed to calcium oxalate (CaOx) crystals and in transgenic mice with induced nephrocalcinosis.
  • Examined autophagy in kidney stone patient samples.
  • Utilized mechanistic target of rapamycin kinase (MTOR) inhibitors to modulate autophagy.
  • Measured crystal-cell interactions and inflammatory responses.

Main Results:

  • Autophagic activity was significantly decreased in mouse RTCs and kidneys with CaOx crystals, and in kidney stone formers.
  • Impaired autophagy led to the accumulation of damaged organelles, indicating compromised cellular function.
  • Decreased autophagy was linked to MTOR upregulation and subsequent suppression of transcription factor EB (TFEB).
  • MTOR inhibition restored autophagy, reduced crystal-cell interactions, and alleviated inflammation.

Conclusions:

  • Compromised autophagy, driven by MTOR deregulation, is a critical factor in kidney stone pathology.
  • MTOR inhibition presents a promising therapeutic strategy for suppressing kidney stone formation.
  • Restoring autophagy via MTOR inhibition could mitigate crystal-cell interactions and associated inflammation.
Keywords:
Autophagycalcium oxalatekidney stonemechanistic target of rapamycin kinasetranscription factor EB

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