Exacerbation of diabetic renal alterations in mice lacking vasohibin-1

Norikazu Hinamoto, Yohei Maeshima, Hiroko Yamasaki, Tatsuyo Nasu, Daisuke Saito, Hiroyuki Watatani, Haruyo Ujike, Katsuyuki Tanabe, Kana Masuda, Yuka Arata, Hitoshi Sugiyama, Yasufumi Sato, Hirofumi Makino

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17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number0107934
JournalPloS one
Volume9
Issue number9
DOIs
Publication statusPublished - 2014 Sep 25

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hinamoto, N., Maeshima, Y., Yamasaki, H., Nasu, T., Saito, D., Watatani, H., Ujike, H., Tanabe, K., Masuda, K., Arata, Y., Sugiyama, H., Sato, Y., & Makino, H. (2014). Exacerbation of diabetic renal alterations in mice lacking vasohibin-1. PloS one, 9(9), [0107934]. https://doi.org/10.1371/journal.pone.0107934