Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: Its implications in tubulointerstitial fibrosis

Ping Xie, Lin Sun, Peter J. Oates, Satish K. Srivastava, Yashpal S. Kanwar

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Renal-specific oxido-reductase/myoinositol oxygenase (RSOR/MIOX) is expressed in renal tubules. It catabolizes myo-inositol and its expression is increased in diabetic mice and in LLC-PK1 cells under high-glucose ambience. Aldose reductase (AR) is another aldo-keto reducase that is expressed in renal tubules. It regulates the polyol pathway and plays an important role in glucose metabolism, osmolyte regulation, and ECM pathobiology via the generation of advanced glycation end products, reactive oxygen species, and activation of transforming growth factor (TGF)-β. In view of the similarities between AR and RSOR/MIOX, the pathobiology of RSOR/MIOX and some of the cellular pathways affected by its overexpression were investigated. An increased expression of fibronectin was noted by transfection of LLC-PK 1 cells with pcDNA3.1-RSOR/MIOX. Similar changes were observed in LLC-PK1 cells under high-glucose ambience, and they were notably lessened by RSOR/MIOX-small interfering (si) RNA treatment. The changes in tubulointerstitial fibronectin expression were also observed in the kidneys of db/db mice having high levels of RSOR. The pcDNA3.1-RSOR/MIOX transfectants had an increased NADH/NAD+ ratio, PKC and TGF-β activity, Raf1:Ras association, and p-ERK phosphorylation. These changes were significantly reduced by the inhibitors of PKC, aldose reductase, Ras farnesylation, and MEK1. Similar increases in various the above-noted parameters were observed under high-glucose ambience. Such changes were partially reversed with RSOR-siRNA treatment. Expression of Ecadherin and vimentin paralleled in cells overexpressing RSOR/ MIOX or subjected to high-glucose ambience. These studies suggest that RSOR/MIOX modulates various downstream pathways affected by high-glucose ambience, and conceivably it plays a role in the pathobiology of tubulointerstitium in diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)F1393-F1404
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 1 2010

Keywords

  • Fibronectin
  • Sorbinil
  • db/db mice

ASJC Scopus subject areas

  • Physiology
  • Urology

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