Cardiovascular Division, King's College London, London, United Kingdom;
J Am Soc Nephrol. 2014 Jan;25(1):33-42. doi: 10.1681/ASN.2012121218. Epub 2013 Sep 5.
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.
血管生长因子在维持肾小球滤过屏障的结构和完整性方面发挥着重要作用。在健康的成年肾小球中，促内皮细胞生存因子血管内皮生长因子-A（VEGF-A）和血管生成素-1 在肾小球足细胞上皮细胞中持续表达。我们证明，这种血管生长因子的环境在链脲佐菌素诱导的 1 型糖尿病小鼠中发生了改变，表现为血管生成素-1 水平降低、VEGF-A 上调、可溶性血管内皮生长因子受体-1（VEGFR1）减少和 VEGFR2 磷酸化增加。这伴随着明显的白蛋白尿、肾脏肿大、高滤过、肾小球超微结构改变和异常血管生成。随后，我们假设在肾小球内恢复血管生成素-1 的表达可能改善早期糖尿病肾小球病变的表现。在糖尿病小鼠中，足细胞特异性诱导补充血管生成素-1 可使白蛋白尿减少 70%，并防止糖尿病引起的肾小球内皮细胞增殖；高滤过和肾脏形态学无变化。此外，糖尿病小鼠中血管生成素-1 的补充增加了 Tie-2 的磷酸化，提高了可溶性 VEGFR1，并伴随着 VEGFR2 磷酸化的减少和内皮型一氧化氮合酶 Ser(1177)磷酸化的增加。在血管生成素-1 补充的小鼠中，糖尿病诱导的nephrin 磷酸化也减少了。总之，靶向血管生成素-1 的治疗方法有望成为糖尿病肾病早期阶段的一种肾脏保护工具。
