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- Title
Vasohibin-1, a Negative Feedback Regulator of Angiogenesis, Ameliorates Renal Alterations in a Mouse Model of Diabetic Nephropathy.
- Authors
Nasu, Tatsuyo; Maeshima, Yohei; Kinomura, Masaru; Hirokoshi-Kawahara, Kumiko; Tanabe, Katsuyuki; Sugiyama, Hitoshi; Sonoda, Hikaru; Sato, Yasufumi; Makino, Hirofumi
- Abstract
OBJECTIVE--The involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model. RESEARCH DESIGN AND METHODS--Streptozotocin-induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or Β-gal (AdLacZ) every other week and were killed after 28 days. RESULTS--Treatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31[sup +] glomerular endothelial area, F4/80[sup +] monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-Β1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-Β, monocyte chemoattractant protein-l, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1-treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice. CONCLUSIONS--These results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells. Diabetes 58:2365-2375, 2009
- Subjects
NEOVASCULARIZATION inhibitors; DIABETIC nephropathies; ANIMAL models of diabetes; LABORATORY mice; VASCULAR endothelial growth factors; MACROPHAGES; TRANSFORMING growth factors
- Publication
Diabetes, 2009, Vol 58, Issue 10, p2365
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db08-1790