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Decrease in transient receptor potential melastatin 6 mRNA stability caused by rapamycin in renal tubular epithelial

Akira Ikari1, Ayumi Sanada, Hayato Sawada

  • 1Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. ikari@u-shizuoka-ken.ac.jp

Biochimica Et Biophysica Acta
|November 16, 2010
PubMed

Insights

Rapamycin, an mTOR inhibitor, reduces magnesium (Mg2+) reabsorption by decreasing TRPM6 expression. This occurs via reduced mRNA stability, not altered transcription, suggesting a PI3K/Akt pathway regulates TRPM6.

Area of Science:

  • Molecular Biology
  • Cell Physiology
  • Pharmacology

Background:

  • Rapamycin (mTOR inhibitor) is used in transplantation and cancer treatments.
  • Rapamycin is known to cause hypomagnesemia (low magnesium levels).
  • The precise mechanism behind rapamycin-induced hypomagnesemia remains unclear.

Purpose of the Study:

  • To investigate the effect of rapamycin on transient receptor potential melastatin 6 (TRPM6) expression.
  • To elucidate the molecular pathway regulating TRPM6 and its connection to rapamycin's action.
  • To understand how rapamycin influences magnesium (Mg2+) transport.

Main Methods:

  • Utilized rat renal NRK-52E epithelial cells.
  • Administered rapamycin, LY-294002 (PI3K inhibitor), U0126 (MEK inhibitor), and Akt inhibitor.
  • Measured TRPM6 and TRPM7 protein expression, Mg2+ influx, and mRNA levels.
  • Assessed effects on signaling pathways (ERK, Akt, c-Fos) and TRPM6 promoter activity.
  • Analyzed mRNA stability using actinomycin D and 3'-untranslated region (UTR) reporter assays.

Main Results:

  • Rapamycin and LY-294002 inhibited epidermal growth factor (EGF)-induced TRPM6 protein expression and Mg2+ influx.
  • The PI3K/Akt pathway, but not ERK/MAPK, was implicated in EGF-induced TRPM6 expression.
  • Rapamycin reduced TRPM6 mRNA levels by decreasing mRNA stability, not transcription, affecting the 3'-UTR.

Conclusions:

  • A PI3K/Akt/mTOR pathway regulates TRPM6 expression.
  • Rapamycin reduces Mg2+ reabsorption by destabilizing TRPM6 mRNA.
  • This study clarifies a mechanism for rapamycin-induced hypomagnesemia.

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