title: Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis.
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)-β1, 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.
authors.affiliation: Dept. of Medicine and Clinical Science, Okayama Univ. Graduate School of Medicine and Dentistry, Okayama, 700-8558, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saito
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.forename: Tatsuyo
authors.initials: T
authors.lastname: Nasu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sonoda
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sato
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese
chemical_list: D020533:Angiogenesis Inhibitors; D001786:Blood Glucose; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C493181:VASH1 protein, human; C113267:nephrin