Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience

Baibaswata Nayak, Ping Xie, Shigeru Akagi, Qiwei Yang, Lin Sun, Jun Wada, Arun Thakur, Farhad R. Danesh, Sumant S. Chugh, Yashpal S. Kanwar

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to D-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl- choline and H2O2. Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.

Original languageEnglish (US)
Pages (from-to)17952-17957
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005

Fingerprint

Inositol Oxygenase
Oxidoreductases
Kidney
Glucose
Response Elements
NFATC Transcription Factors
Aldehyde Reductase
Carrier Proteins
Carbohydrates
Osmoregulation
Sorbitol
Inositol
Choline
Protein Binding
Oxidants
Type 2 Diabetes Mellitus
Genes

Keywords

  • Diabetic nephropathy
  • Hyperglycemia
  • Osmoregulation

ASJC Scopus subject areas

  • General

Cite this

Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. / Nayak, Baibaswata; Xie, Ping; Akagi, Shigeru; Yang, Qiwei; Sun, Lin; Wada, Jun; Thakur, Arun; Danesh, Farhad R.; Chugh, Sumant S.; Kanwar, Yashpal S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 50, 13.12.2005, p. 17952-17957.

Research output: Contribution to journalArticle

Nayak, B, Xie, P, Akagi, S, Yang, Q, Sun, L, Wada, J, Thakur, A, Danesh, FR, Chugh, SS & Kanwar, YS 2005, 'Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 50, pp. 17952-17957. https://doi.org/10.1073/pnas.0509089102
Nayak, Baibaswata ; Xie, Ping ; Akagi, Shigeru ; Yang, Qiwei ; Sun, Lin ; Wada, Jun ; Thakur, Arun ; Danesh, Farhad R. ; Chugh, Sumant S. ; Kanwar, Yashpal S. / Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 50. pp. 17952-17957.
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AU - Akagi, Shigeru

AU - Yang, Qiwei

AU - Sun, Lin

AU - Wada, Jun

AU - Thakur, Arun

AU - Danesh, Farhad R.

AU - Chugh, Sumant S.

AU - Kanwar, Yashpal S.

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AB - Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to D-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl- choline and H2O2. Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.

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