Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy

Tatsuyo Nasu, Yohei Maeshima, Masaru Kinomura, Kumiko Hirokoshi-Kawahara, Katsuyuki Tanabe, Hitoshi Sugiyama, Hikaru Sonoda, Yasufumi Sato, Hirofumi Makino

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE - The involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model. RESEARCH DESIGN AND METHODS - Streptozotocin-induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or β-gal (Ad-LacZ) every other week and were killed after 28 days. RESULTS - Treatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-β1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-β, monocyte chemoattractant protein-1, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1-treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice. CONCLUSIONS - These results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells.

Original languageEnglish
Pages (from-to)2365-2375
Number of pages11
JournalDiabetes
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 2009

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Diabetic Nephropathies
Kidney
CCR2 Receptors
Angiogenesis Inhibitors
Mesangial Cells
Endothelial Cells
Transforming Growth Factors
Hypertrophy
Therapeutics
Albuminuria
Collagen Type IV
Streptozocin
Intravenous Injections
Vascular Endothelial Growth Factor A
Real-Time Polymerase Chain Reaction
Monocytes
Research Design
Macrophages
Phosphorylation
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. / Nasu, Tatsuyo; Maeshima, Yohei; Kinomura, Masaru; Hirokoshi-Kawahara, Kumiko; Tanabe, Katsuyuki; Sugiyama, Hitoshi; Sonoda, Hikaru; Sato, Yasufumi; Makino, Hirofumi.

In: Diabetes, Vol. 58, No. 10, 10.2009, p. 2365-2375.

Research output: Contribution to journalArticle

Nasu, Tatsuyo ; Maeshima, Yohei ; Kinomura, Masaru ; Hirokoshi-Kawahara, Kumiko ; Tanabe, Katsuyuki ; Sugiyama, Hitoshi ; Sonoda, Hikaru ; Sato, Yasufumi ; Makino, Hirofumi. / Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. In: Diabetes. 2009 ; Vol. 58, No. 10. pp. 2365-2375.
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T1 - Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy

AU - Nasu, Tatsuyo

AU - Maeshima, Yohei

AU - Kinomura, Masaru

AU - Hirokoshi-Kawahara, Kumiko

AU - Tanabe, Katsuyuki

AU - Sugiyama, Hitoshi

AU - Sonoda, Hikaru

AU - Sato, Yasufumi

AU - Makino, Hirofumi

PY - 2009/10

Y1 - 2009/10

N2 - OBJECTIVE - The involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model. RESEARCH DESIGN AND METHODS - Streptozotocin-induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or β-gal (Ad-LacZ) every other week and were killed after 28 days. RESULTS - Treatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-β1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-β, monocyte chemoattractant protein-1, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1-treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice. CONCLUSIONS - These results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells.

AB - OBJECTIVE - The involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model. RESEARCH DESIGN AND METHODS - Streptozotocin-induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or β-gal (Ad-LacZ) every other week and were killed after 28 days. RESULTS - Treatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-β1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-β, monocyte chemoattractant protein-1, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1-treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice. CONCLUSIONS - These results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells.

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