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Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

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 en...

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Autores principales: Hinamoto, Norikazu, Maeshima, Yohei, Yamasaki, Hiroko, Nasu, Tatsuyo, Saito, Daisuke, Watatani, Hiroyuki, Ujike, Haruyo, Tanabe, Katsuyuki, Masuda, Kana, Arata, Yuka, Sugiyama, Hitoshi, Sato, Yasufumi, Makino, Hirofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178006/
https://www.ncbi.nlm.nih.gov/pubmed/25255225
http://dx.doi.org/10.1371/journal.pone.0107934
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author Hinamoto, Norikazu
Maeshima, Yohei
Yamasaki, Hiroko
Nasu, Tatsuyo
Saito, Daisuke
Watatani, Hiroyuki
Ujike, Haruyo
Tanabe, Katsuyuki
Masuda, Kana
Arata, Yuka
Sugiyama, Hitoshi
Sato, Yasufumi
Makino, Hirofumi
author_facet Hinamoto, Norikazu
Maeshima, Yohei
Yamasaki, Hiroko
Nasu, Tatsuyo
Saito, Daisuke
Watatani, Hiroyuki
Ujike, Haruyo
Tanabe, Katsuyuki
Masuda, Kana
Arata, Yuka
Sugiyama, Hitoshi
Sato, Yasufumi
Makino, Hirofumi
author_sort Hinamoto, Norikazu
collection PubMed
description 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. Streptozotocin-induced 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-κB 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 IκBα, 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-β(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.
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spelling pubmed-41780062014-10-02 Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1 Hinamoto, Norikazu Maeshima, Yohei Yamasaki, Hiroko Nasu, Tatsuyo Saito, Daisuke Watatani, Hiroyuki Ujike, Haruyo Tanabe, Katsuyuki Masuda, Kana Arata, Yuka Sugiyama, Hitoshi Sato, Yasufumi Makino, Hirofumi PLoS One Research Article 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. Streptozotocin-induced 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-κB 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 IκBα, 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-β(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. Public Library of Science 2014-09-25 /pmc/articles/PMC4178006/ /pubmed/25255225 http://dx.doi.org/10.1371/journal.pone.0107934 Text en © 2014 Hinamoto et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hinamoto, Norikazu
Maeshima, Yohei
Yamasaki, Hiroko
Nasu, Tatsuyo
Saito, Daisuke
Watatani, Hiroyuki
Ujike, Haruyo
Tanabe, Katsuyuki
Masuda, Kana
Arata, Yuka
Sugiyama, Hitoshi
Sato, Yasufumi
Makino, Hirofumi
Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title_full Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title_fullStr Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title_full_unstemmed Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title_short Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1
title_sort exacerbation of diabetic renal alterations in mice lacking vasohibin-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178006/
https://www.ncbi.nlm.nih.gov/pubmed/25255225
http://dx.doi.org/10.1371/journal.pone.0107934
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