Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells

Potential role in diabetic nephropathy

Shinsuke Kiritoshi, Takeshi Nishikawa, Kazuhiro Sonoda, Daisuke Kukidome, Takahumi Senokuchi, Tomoko Matsuo, Takeshi Matsumura, Hiroshi Tokunaga, Michael Brownlee, Eiichi Araki

Research output: Contribution to journalArticle

243 Citations (Scopus)

Abstract

Hyperglycemia increases the production of reactive oxygen species (ROS) from the mitochondrial electron transport chain in bovine endothelial cells. Because several studies have postulated a role for prostaglandins (PGs) in the glomerular hyperfiltration seen in early diabetes, we evaluated the effect of mitochondrial ROS on expression of the inducible isoform of cyclooxygenase (COX-2) in cultured human mesangial cells (HMCs). We first confirmed that incubation of HMC with 30 mmol/l glucose significantly increased COX-2 mRNA but not COX-1 mRNA, compared with 5.6 mmol/l glucose. Similarly, incubation of HMCs with 30 mmol/l glucose significantly increased mitochondrial membrane potential, intracellular ROS production, COX-2 protein expression, and PGE2 synthesis, and these events were completely suppressed by thenoyltrifluoroacetone or carbonyl cyanide m-chlorophenylhydrazone, inhibitors of mitochondrial metabolism, or by overexpression of uncoupling protein-1 or manganese superoxide dismutase. Furthermore, increased expression of COX-2 mRNA and protein was confirmed in glomeruli of streptozotocin-induced diabetic mice. In addition, hyperglycemia induced activation of the COX-2 gene promoter, which was completely abrogated by mutation of two nuclear factor κB (NF-κB) binding sites in the promoter region. Our results suggest that hyperglycemia increases mitochondrial ROS production, resulting in NF-κB activation, COX-2 mRNA induction, COX-2 protein production, and PGE2 synthesis. This chain of events might contribute to the pathogenesis of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)2570-2577
Number of pages8
JournalDiabetes
Volume52
Issue number10
DOIs
StatePublished - Oct 1 2003

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Mesangial Cells
Diabetic Nephropathies
Cyclooxygenase 2
Reactive Oxygen Species
Mitochondria
Hyperglycemia
Gene Expression
Messenger RNA
Dinoprostone
Glucose
Thenoyltrifluoroacetone
Proteins
Mitochondrial Membrane Potential
Streptozocin
Electron Transport
Genetic Promoter Regions
Superoxide Dismutase
Prostaglandins
Protein Isoforms
Endothelial Cells

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells : Potential role in diabetic nephropathy. / Kiritoshi, Shinsuke; Nishikawa, Takeshi; Sonoda, Kazuhiro; Kukidome, Daisuke; Senokuchi, Takahumi; Matsuo, Tomoko; Matsumura, Takeshi; Tokunaga, Hiroshi; Brownlee, Michael; Araki, Eiichi.

In: Diabetes, Vol. 52, No. 10, 01.10.2003, p. 2570-2577.

Research output: Contribution to journalArticle

Kiritoshi, S, Nishikawa, T, Sonoda, K, Kukidome, D, Senokuchi, T, Matsuo, T, Matsumura, T, Tokunaga, H, Brownlee, M & Araki, E 2003, 'Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: Potential role in diabetic nephropathy', Diabetes, vol. 52, no. 10, pp. 2570-2577. https://doi.org/10.2337/diabetes.52.10.2570
Kiritoshi, Shinsuke ; Nishikawa, Takeshi ; Sonoda, Kazuhiro ; Kukidome, Daisuke ; Senokuchi, Takahumi ; Matsuo, Tomoko ; Matsumura, Takeshi ; Tokunaga, Hiroshi ; Brownlee, Michael ; Araki, Eiichi. / Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells : Potential role in diabetic nephropathy. In: Diabetes. 2003 ; Vol. 52, No. 10. pp. 2570-2577.
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