Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

Daisuke Saito, Yohei Maeshima, Tatsuyo Nasu, Hiroko Yamasaki, Katsuyuki Abe, Hitoshi Sugiyama, Hikaru Sonoda, Yasufumi Sato, Hirofumi Makino

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Abstract

The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365-2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-(31, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1+) and desmin+ podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

Original languageEnglish
Pages (from-to)873-886
Number of pages14
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number4
DOIs
Publication statusPublished - Apr 1 2011

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Podocytes
Kidney
Diabetic Nephropathies
Vascular Endothelial Growth Factor A
Angiogenesis Inhibitors
Desmin
Zonula Occludens-1 Protein
Therapeutics
Glucose
Obese Mice
Vascular Endothelial Growth Factor Receptor-2
Gastropoda
Albuminuria
Collagen Type IV
Chemokine CCL2
Tight Junctions
Transforming Growth Factors
Therapeutic Uses
Cadherins
Immunoblotting

Keywords

  • Podocyte
  • Proteinuria

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis. / Saito, Daisuke; Maeshima, Yohei; Nasu, Tatsuyo; Yamasaki, Hiroko; Abe, Katsuyuki; Sugiyama, Hitoshi; Sonoda, Hikaru; Sato, Yasufumi; Makino, Hirofumi.

In: American Journal of Physiology - Renal Physiology, Vol. 300, No. 4, 01.04.2011, p. 873-886.

Research output: Contribution to journalArticle

Saito, Daisuke ; Maeshima, Yohei ; Nasu, Tatsuyo ; Yamasaki, Hiroko ; Abe, Katsuyuki ; Sugiyama, Hitoshi ; Sonoda, Hikaru ; Sato, Yasufumi ; Makino, Hirofumi. / Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis. In: American Journal of Physiology - Renal Physiology. 2011 ; Vol. 300, No. 4. pp. 873-886.
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