A novel preventive mechanism of gentamicin-induced nephrotoxicity by atorvastatin

Mei Chun Lee, Kuei Ju Cheng, Shih Ming Chen, Yi Chieh Li, Kazuhiro Imai, Chun Ming Lee, Jen Ai Lee

Research output: Contribution to journalArticle

Abstract

Atorvastatin (ATO) inhibits the synthesis of nonsteroidal isoprenoid compounds and possesses a pleiotropic effect. However, the detailed mechanism of ATO in preventing gentamicin (GM)-induced renal injury remains obscure. Although underlying multifaceted mechanisms involving GM-induced nephrotoxicity were well known, further work on elucidating the essential mechanism was needed. Using a fluorogenic derivatization–liquid chromatography tandem mass spectrometry proteomic method (FD-LC–MS/MS method), we investigated the effects and mechanisms of ATO treatment on GM-induced nephrotoxicity in rats. Consequently, 49 differentially expressed proteins were identified. The most significant mechanisms of nephrotoxicity caused by GM were mitochondrial dysfunction, fatty acid metabolism and oxidative stress. Their upstream regulator was found to be PPARα. The proteins involved in GM nephrotoxicity were sodium–hydrogen exchanger regulatory factor (SLC9A3R1), cathepsin V (CTSV), macrophage migration inhibitory factor (MIF) and RhoGDP dissociation inhibitor alpha (ARHGDIA). After ATO intervention, we observed a reversed enrichment pattern of their expression, especially in CTSV and SLC9A3R1 (P-value<0.05). We predicted that ATO may improve abnormal phospholipid metabolism and phospholipidosis caused by GM and also alleviate cell volume homeostasis and reverse the interference of GM with the transporter. Furthermore, proteomic results also provided clues as to GM-induced nephrotoxicity biomarkers such as CTSV and transthyretin.

Original languageEnglish
Article numbere4639
JournalBiomedical Chromatography
DOIs
Publication statusPublished - Jan 1 2019

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Gentamicins
Cathepsins
Metabolism
Proteomics
Macrophage Migration-Inhibitory Factors
Peroxisome Proliferator-Activated Receptors
Prealbumin
Oxidative stress
Atorvastatin Calcium
Terpenes
Biomarkers
Tandem Mass Spectrometry
Chromatography
Cell Size
Mass spectrometry
Rats
Phospholipids
Proteins
Oxidative Stress
Homeostasis

Keywords

  • atorvastatin
  • DAABD-cl
  • gentamicin
  • nephrotoxicity

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

A novel preventive mechanism of gentamicin-induced nephrotoxicity by atorvastatin. / Lee, Mei Chun; Cheng, Kuei Ju; Chen, Shih Ming; Li, Yi Chieh; Imai, Kazuhiro; Lee, Chun Ming; Lee, Jen Ai.

In: Biomedical Chromatography, 01.01.2019.

Research output: Contribution to journalArticle

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