Loss of NRF2 impairs gastric nitrergic stimulation and function

Sutapa Mukhopadhyay, Konjeti R. Sekhar, Ashley B. Hale, Keith M. Channon, Gianrico Farrugia, Michael L. Freeman, Pandu R. Gangula

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Emerging research suggests that antioxidant gene expression has the potential to suppress the development of gastroparesis. However, direct genetic evidence that definitively supports this concept is lacking. We used mice carrying a targeted disruption of Nfe2l2, the gene that encodes the transcription factor NRF2 and directs antioxidant Phase II gene expression, as well as mice with a targeted disruption of Gclm, the modifier subunit for glutamate-cysteine ligase, to test the hypothesis that defective antioxidant gene expression contributes to development of gastroparesis. Although expression of heme oxygenase-1 remained unchanged, expression of GCLC, GCLM, SOD1, and CAT was down-regulated in gastric tissue from Nrf2 -/- mice compared to wild-type animals. Tetrahydrobiopterin oxidation was significantly elevated and nitrergic relaxation was impaired in Nrf2 -/- mouse gastric tissue. In vitro studies showed a significant decrease in NO release in Nrf2 -/- mouse gastric tissue. Nrf2 -/- mice displayed delayed gastric emptying. The use of Gclm -/- mice demonstrated that the loss of glutamate-cysteine ligase function enhanced tetrahydrobiopterin oxidation while impairing nitrergic relaxation. These results provide genetic evidence that loss of antioxidant gene expression can contribute to the development of gastroparesis and suggest that NRF2 represents a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)619-625
Number of pages7
JournalFree Radical Biology and Medicine
Volume51
Issue number3
DOIs
StatePublished - Aug 1 2011

Fingerprint

Gene expression
Stomach
Antioxidants
Glutamate-Cysteine Ligase
Gastroparesis
Tissue
Gene Expression
Oxidation
Heme Oxygenase-1
Animals
Transcription Factors
Genes
Wild Animals
Gastric Emptying
sapropterin
Research

Keywords

  • Free radicals
  • Gastric motility
  • Gastroparesis
  • GCLC
  • GCLM
  • Mice
  • Nitric oxide
  • nNOSα
  • NRF2

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Mukhopadhyay, S., Sekhar, K. R., Hale, A. B., Channon, K. M., Farrugia, G., Freeman, M. L., & Gangula, P. R. (2011). Loss of NRF2 impairs gastric nitrergic stimulation and function. Free Radical Biology and Medicine, 51(3), 619-625. https://doi.org/10.1016/j.freeradbiomed.2011.04.044

Loss of NRF2 impairs gastric nitrergic stimulation and function. / Mukhopadhyay, Sutapa; Sekhar, Konjeti R.; Hale, Ashley B.; Channon, Keith M.; Farrugia, Gianrico; Freeman, Michael L.; Gangula, Pandu R.

In: Free Radical Biology and Medicine, Vol. 51, No. 3, 01.08.2011, p. 619-625.

Research output: Contribution to journalArticle

Mukhopadhyay, S, Sekhar, KR, Hale, AB, Channon, KM, Farrugia, G, Freeman, ML & Gangula, PR 2011, 'Loss of NRF2 impairs gastric nitrergic stimulation and function', Free Radical Biology and Medicine, vol. 51, no. 3, pp. 619-625. https://doi.org/10.1016/j.freeradbiomed.2011.04.044
Mukhopadhyay, Sutapa ; Sekhar, Konjeti R. ; Hale, Ashley B. ; Channon, Keith M. ; Farrugia, Gianrico ; Freeman, Michael L. ; Gangula, Pandu R. / Loss of NRF2 impairs gastric nitrergic stimulation and function. In: Free Radical Biology and Medicine. 2011 ; Vol. 51, No. 3. pp. 619-625.
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