2014年9月
Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
PLOS ONE
- 巻
- 9
- 号
- 9
- 開始ページ
- e107934
- 終了ページ
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1371/journal.pone.0107934
- 出版者・発行元
- PUBLIC LIBRARY SCIENCE
Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocininduced type 1 diabetic VASH1 heterozygous knockout mice (VASH1(+/-)) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1(+/-) mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-kappa B p65 were significantly exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of I kappa B alpha, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31(+) endothelial area was also increased in the diabetic VASH1(+/-) mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-beta(1)/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.
- リンク情報
- ID情報
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- DOI : 10.1371/journal.pone.0107934
- ISSN : 1932-6203
- PubMed ID : 25255225
- Web of Science ID : WOS:000344862300045