title: Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model.
abstract: Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31(+)), and F4/80(+) monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-beta1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide-treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeshima
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitayama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takazawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hirokoshi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000419:Albuminuria; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D024141:Collagen Type IV / Q000032:analysis; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D043169:Endostatins / Q000032:analysis / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy; D006984:Hypertrophy; D007150:Immunohistochemistry; D039081:Integrin alpha5beta1 / Q000032:analysis; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009929:Organ Size; D010446:Peptide Fragments / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D001786:Blood Glucose; D024141:Collagen Type IV; D043169:Endostatins; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D003404:Creatinine; D040301:Vascular Endothelial Growth Factor Receptor-2