Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease
Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease
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DOI：
10.1681/asn.2012121218
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发表时间：
2014-01-01
影响因子：
13.6
通讯作者：
Gnudi, Luigi
中科院分区：
文献类型：
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作者：
Dessapt-Baradez, Cecile;Woolf, Adrian S.;Gnudi, Luigi
血管生长因子在维持肾小球滤过屏障的结构和完整性中起重要作用。在健康成人肾小球中，促内皮细胞存活因子血管内皮生长因子-A（VEGF-A）和血管生成素-1组成型表达于肾小球足细胞上皮。我们证明，在链脲佐菌素诱导的1型糖尿病小鼠中，血管生长因子的这种环境发生了改变，血管生成素-1水平降低，VEGF-A上调，可溶性VEGF受体-1（VEGFR 1）降低，VEGFR 2磷酸化增加。这伴随着明显的蛋白尿、肾肥大、超滤、肾小球超微结构改变和异常血管生成。我们随后假设肾小球内血管生成素-1表达的恢复可能会改善早期糖尿病肾小球病变的表现。足细胞特异性诱导的血管生成素-1在糖尿病小鼠中的补充导致蛋白尿减少70%，并阻止糖尿病诱导的肾小球内皮细胞增殖;超滤和肾脏形态学无变化。此外，在糖尿病小鼠中，血管生成素-1补充增加Tie-2磷酸化，升高可溶性VEGFR 1，并且被VEGFR 2磷酸化减少和内皮一氧化氮合酶Ser（1177）磷酸化增加所抵消。糖尿病诱导的nephrin磷酸化在血管生成素-1补充的小鼠中也减少。总之，靶向血管生成素-1治疗显示出作为糖尿病肾病早期肾脏保护工具的前景。
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.