Myo-inositol oxygenase accentuates renal tubular injury initiated by endoplasmic reticulum stress

Tatsuya Tominaga, Isha Sharma, Yui Fujita, Toshio Doi, Aryana K. Wallner, Yashpal S. Kanwar

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Besides oxidant stress, endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various metabolic disorders affecting the kidney. These two forms of stresses are not mutually exclusive to each other and may operate by a feedback loop in worsening the cellular injury. To attest to this contention, studies were performed to assess whether in such a setting, there is worsening of tubulointerstitial injury. We employed tunicamycin as a model of ER stress and used tubular cells and mice overexpressing myo-inositol oxygenase (MIOX), an enzyme involved in glycolytic events with excessive generation of ROS. Concomitant treatment of tunicamycin and transfection of cells with MIOX-pcDNA led to a marked generation of ROS, which was reduced by MIOX-siRNA. Likewise, an accentuated expression of ER stress sensors, GRP78, XBP1, and CHOP, was observed, which was reduced with MIOX-siRNA. These sensors were markedly elevated in MIOX-TG mice compared with WT treated with tunicamycin. This was accompanied with marked deterioration of tubular morphology, along with impairment of renal functions. Interestingly, minimal damage and elevation of ER stressors was observed in MIOX-KO mice. Downstream events that were more adversely affected in MIOX-TG mice included accentuated expression of proapoptogenic proteins, proinflammatory cytokines, and extracellular matrix constituents, although expression of these molecules was unaffected in MIOX-KO mice. Also, their tunicamycin-induced accentuated expression in tubular cells was notably reduced with MIOX-siRNA. These studies suggest that the biology of MIOX-induced oxidant stress and tunicamycin-induced ER stress are interlinked, and both of the events may feed into each other to amplify the tubulointerstitial injury.

Original languageEnglish (US)
Pages (from-to)F301-F315
JournalAmerican Journal of Physiology - Renal Physiology
Volume316
Issue number2
DOIs
StatePublished - 2019

Keywords

  • ER stress
  • Hyaluronic acid
  • Myo-inositol oxygenase

ASJC Scopus subject areas

  • Physiology
  • Urology

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