title: Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy.
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.
  
  
  METHODS
  Streptozotocin- induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or beta-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(+) glomerular endothelial area, F4/80(+) 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-beta1, 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-beta, monocyte chemoattractant protein-1, 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.
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Tatsuyo
authors: T
authors: Nasu
authors: Yohei
authors: Y
authors: Maeshima
authors: Masaru
authors: M
authors: Kinomura
authors: Kumiko
authors: K
authors: Hirokoshi-Kawahara
authors: Katsuyuki
authors: K
authors: Tanabe
authors: Hitoshi
authors: H
authors: Sugiyama
authors: Hikaru
authors: H
authors: Sonoda
authors: Yasufumi
authors: Y
authors: Sato
authors: Hirofumi
authors: H
authors: Makino
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D018797:Cell Cycle Proteins / Q000235:genetics / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005822:Genetic Vectors; D007668:Kidney / Q000033:anatomy & histology; D007672:Kidney Cortex / Q000502:physiology / Q000503:physiopathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; C493181:VASH1 protein, human