Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy.
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.
Nasu
Tatsuyo
T
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Maeshima
Yohei
Y
Kinomura
Masaru
M
Hirokoshi-Kawahara
Kumiko
K
Tanabe
Katsuyuki
K
Sugiyama
Hitoshi
H
Sonoda
Hikaru
H
Sato
Yasufumi
Y
Makino
Hirofumi
H
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
D020533:Angiogenesis Inhibitors; C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; C493181:VASH1 protein, human