2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice

Kunihiro Ichinose, Yohei Maeshima, Yoshihiko Yamamoto, Masaru Kinomura, Kumiko Hirokoshi, Hiroyuki Kitayama, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, Naoki Agata, Hirofumi Makino

Research output: Contribution to journalArticle

Abstract

One of the mechanisms involved in the progression of diabetic nephropathy, the most common cause of end-stage renal failure, is angiogenic phenomenon associated with the increase of angiogenic factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2, an antagonist of Ang-1. In the present study, we examined the therapeutic efficacy of 2-(8-hydroxy-6-methoxy-1- oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3), a small molecule isocoumarin with antiangiogenic activity, using diabetic db/db mice, a model of obese type 2 diabetes. Increases in kidney weight, glomerular volume, creatinine clearance, urinary albumin excretion, total mesangial fraction, glomerular type IV collagen, glomerular endothelial area (CD31+), and monocyte/macrophage accumulation (F4/80+) observed in control db/db mice were significantly suppressed by daily intraperitoneal injection of NM-3 (100 mg/kg, for 8 weeks). Increases in renal expression of VEGF-A, Ang-2, fibrogenic factor transforming growth factor (TGF)-β1, and chemokine monocyte chemoattractant protein-1 but not tumor necrosis factor-α were also inhibited by NM-3 in db/db mice. Furthermore, decreases of nephrin mRNA and protein levels in db/db mice were recovered by NM-3. In addition, treatment of db/db mice with NM-3 did not affect body weight, blood glucose, serum insulin, or food consumption. NM-3 significantly suppressed the increase of VEGF induced by high glucose in cultured podocytes and also suppressed the increase of VEGF and TGF-β induced by high glucose in cultured mesangial cells. Taken together, these results demonstrate the potential use of NM-3 as a novel therapeutic agent for renal alterations in type 2 diabetes.

Original languageEnglish
Pages (from-to)1232-1242
Number of pages11
JournalDiabetes
Volume55
Issue number5
DOIs
Publication statusPublished - 2006

Keywords

  • Ang, angiopoietin
  • CCr, creatinine clearance
  • ESRD, end-stage renal disease
  • GBM, glomerular basement membrane
  • IL-6, interleukin-6
  • MCP-1, monocyte chemoattractant protein-1
  • NM-3, 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3- yl) propionic acid

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Ichinose, K., Maeshima, Y., Yamamoto, Y., Kinomura, M., Hirokoshi, K., Kitayama, H., Takazawa, Y., Sugiyama, H., Yamasaki, Y., Agata, N., & Makino, H. (2006). 2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice. Diabetes, 55(5), 1232-1242. https://doi.org/10.2337/diabetes.