TY - JOUR
T1 - Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy
T2 - Its implications in tubulointerstitial fibrosis
AU - Xie, Ping
AU - Sun, Lin
AU - Oates, Peter J.
AU - Srivastava, Satish K.
AU - Kanwar, Yashpal S.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Fibronectin
KW - Sorbinil
KW - db/db mice
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U2 - 10.1152/ajprenal.00137.2010
DO - 10.1152/ajprenal.00137.2010
M3 - Article
C2 - 20335317
AN - SCOPUS:77952681746
SN - 1931-857X
VL - 298
SP - F1393-F1404
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6
ER -