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. RESEARCH DESIGN AND 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.

journal_name

Diabetes

journal_title

Diabetes

authors

Nasu T,Maeshima Y,Kinomura M,Hirokoshi-Kawahara K,Tanabe K,Sugiyama H,Sonoda H,Sato Y,Makino H

doi

10.2337/db08-1790

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

2365-75

issue

10

eissn

0012-1797

issn

1939-327X

pii

db08-1790

journal_volume

58

pub_type

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