Inhibition of arginase ameliorates experimental ulcerative colitis in mice

Y. Akazawa, M. Kubo, R. Zhang, K. Matsumoto, F. Yan, H. Setiawan, H. Takahashi, Y. Fujikura, K. Ogino

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Abstract

Nitric oxide (NO) is produced from the conversion of L-arginine by NO synthase (NOS) and regulates a variety of processes in the gastrointestinal tract. Considering the increased activity of arginase in colitis tissue, it is speculated that arginase could inhibit NO synthesis by competing for the same L-arginine substrate, resulting in the exacerbation of colitis. We examined the role of arginase and its relationship to NO metabolism in dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in mice by administration of 2.5% DSS in drinking water for 8 days. Treatment for arginase inhibition was done by once daily intraperitoneal injection of N ω-hydroxy-nor- arginine (nor-NOHA). On day 8, we evaluated clinical parameters (body weight, disease activity index, and colon length), histological features, the activity and expression of arginase, L-arginine content, the expression of NO synthase (NOS), and the concentration of NO end-product (NOx: nitrite + nitrate). Administration of nor-NOHA improved the worsened clinical parameters and histological features in DSS-induced colitis. Treatment with nor-NOHA attenuated the increased activity of arginase, upregulation of arginase at both mRNA and protein levels, and decreased the content of L-arginine in colonic tissue in the DSS-treated mice. Conversely, despite the decreased expression of NOS2 mRNA, the decreased concentration of NOx in colonic tissues was restored to almost normal levels. The consumption of L-arginine by arginase could lead to decreased production of NO from NOS, contributing to the pathogenesis of the colonic inflammation; thus, arginase inhibition might be effective for improving colitis.

Original languageEnglish
Pages (from-to)137-145
Number of pages9
JournalFree Radical Research
Volume47
Issue number3
DOIs
Publication statusPublished - Feb 18 2013

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Keywords

  • Dextran sulfate sodium
  • L-arginine
  • N-hydroxy-nor-L-arginine
  • NOx
  • Nitric oxide

ASJC Scopus subject areas

  • Biochemistry

Cite this

Akazawa, Y., Kubo, M., Zhang, R., Matsumoto, K., Yan, F., Setiawan, H., Takahashi, H., Fujikura, Y., & Ogino, K. (2013). Inhibition of arginase ameliorates experimental ulcerative colitis in mice. Free Radical Research, 47(3), 137-145. https://doi.org/10.3109/10715762.2012.756980