Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization
Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization
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DOI：
10.1161/hypertensionaha.119.13469
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发表时间：
2019-11-01
期刊：
影响因子：
8.3
通讯作者：
Chade, Alejandro R.
中科院分区：
文献类型：
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作者：
Engel, Jason E.;Williams, Erika;Chade, Alejandro R.
慢性肾脏疾病（CKD）普遍与肾脏微血管稀疏和炎症有关，但这两个过程之间是否存在联系尚不清楚。我们设计了一种治疗性构建体VEGF（血管内皮生长因子）融合到ELP（弹性蛋白样多肽）载体，并表明它可以改善实验性肾血管疾病的肾功能。我们测试了ELP-VEGF治疗将改善CKD的假设，并且恢复将通过部分地通过调节巨噬细胞表型和炎症来减少微血管稀疏来驱动。14头猪诱导CKD，观察14周。在6周时，使用多探测器计算机断层扫描定量肾血流量和滤过，然后猪接受单次肾内ELP-VEGF或安慰剂（各n = 7）。4周和8周后再次定量肾功能。对猪实施安乐死，并对肾微血管密度、血管生成和炎症标志物、纤维化、巨噬细胞浸润和表型进行定量。CKD患者的肾血流动力学损失通过ELP-VEGF治疗逐渐恢复，并伴有肾微血管密度、纤维化和炎症介质表达的改善。虽然肾脏巨噬细胞浸润在两个CKD组中相似，但ELP-VEGF治疗明显将其表型从促炎性M1转移到VEGF表达M2。我们的研究揭示了使用药物递送技术抵消CKD进展的新策略的潜在机制和可行性。结果表明，在CKD中，ELP-VEGF治疗后的肾恢复主要是由肾巨噬细胞向VEGF表达M2表型的调节、恢复VEGF信号传导和维持肾功能和微血管完整性的改善驱动的。
Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.