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.