TY - JOUR
T1 - Exacerbation of diabetic renal alterations in mice lacking vasohibin-1
AU - Hinamoto, Norikazu
AU - Maeshima, Yohei
AU - Yamasaki, Hiroko
AU - Nasu, Tatsuyo
AU - Saito, Daisuke
AU - Watatani, Hiroyuki
AU - Ujike, Haruyo
AU - Tanabe, Katsuyuki
AU - Masuda, Kana
AU - Arata, Yuka
AU - Sugiyama, Hitoshi
AU - Sato, Yasufumi
AU - Makino, Hirofumi
N1 - Funding Information:
The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: Prof. Yohei Maeshima belongs to endowed department by Chugai pharmaceutical, MSD, Boehringer ingelheim and Kawanishi Holdings. Prof. Hitoshi Sugiyama belongs to endowed department by Baxter. Prof. Hirofumi Makino is a consultant for AbbVie, Astellas and Teijin, receives speaker honoraria from Astellas, Boehringer-ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda and Tanabe Mitsubishi, and receives grant support from Astellas, Boehringer-ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, Mochida, MSD, Novartis, Novo Nordisk, Pfizer, Takeda and Tanabe Mitsubishi. Any other authors don’t have competing interests. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2014 Hinamoto et al.
PY - 2014/9/25
Y1 - 2014/9/25
N2 - 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-β1/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.
AB - 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-β1/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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U2 - 10.1371/journal.pone.0107934
DO - 10.1371/journal.pone.0107934
M3 - Article
C2 - 25255225
AN - SCOPUS:84907478555
SN - 1932-6203
VL - 9
JO - PLoS One
JF - PLoS One
IS - 9
M1 - 0107934
ER -
