期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 25, 期 1, 页码 33-42出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2012121218
关键词
-
资金
- Diabetes UK [08/0003695]
- BBSRC [S13745]
- EFSD/Servier
- George M. O'Brien Kidney Research Core Centre [P30-DK081943]
- KRUK Senior Non-Clinical Fellowship
- MRC New Investigator Award
- Manchester Biomedical Research Centre
- Manchester Academic Health Science Centre
- Diabetes UK [08/0003695] Funding Source: researchfish
- Kidney Research UK [RP38/2013, RP18/2011, SF1/2008] Funding Source: researchfish
- Medical Research Council [MR/J003638/1] Funding Source: researchfish
- MRC [MR/J003638/1] Funding Source: UKRI
Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser(1177) phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据