Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom.
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
PLoS One. 2019 Mar 13;14(3):e0212910. doi: 10.1371/journal.pone.0212910. eCollection 2019.
There is evidence to suggest that abnormal angiogenesis, inflammation, and fibrosis drive diabetic nephropathy (DN). However, there is no specific treatment to counteract these processes. We aimed to determine whether DIAVIT, a natural Vaccinium myrtillus (blueberry) and Hippophae Rhamnoides (sea buckthorn) extract, is protective in a model of type II DN. Diabetic db/db mice were administered DIAVIT in their drinking water for 14 weeks. We assessed the functional, structural, and ultra-structural phenotype of three experimental groups (lean+vehicle, db/db+vehicle, db/db+DIAVIT). We also investigated the angiogenic and fibrotic pathways involved in the mechanism of action of DIAVIT. Diabetic db/db mice developed hyperglycaemia, albuminuria, and an increased glomerular water permeability; the latter two were prevented by DIAVIT. db/db mice developed fibrotic glomeruli, endothelial insult, and glomerular ultra-structural changes, which were not present in DIAVIT-treated mice. Vascular endothelial growth factor A (VEGF-A) splicing was altered in the db/db kidney cortex, increasing the pro-angiogenic VEGF-A165 relative to the anti-angiogenic VEGF-A165b. This was partially prevented with DIAVIT treatment. Delphinidin, an anthocyanin abundant in DIAVIT, increased the VEGF-A165b expression relative to total VEGF-A165 in cultured podocytes through phosphorylation of the splice factor SRSF6. DIAVIT, in particular delphinidin, alters VEGF-A splicing in type II DN, rescuing the DN phenotype. This study highlights the therapeutic potential of natural drugs in DN through the manipulation of gene splicing and expression.
有证据表明，异常的血管生成、炎症和纤维化是导致糖尿病肾病（DN）的原因。然而，目前还没有专门的治疗方法来对抗这些过程。我们旨在确定 DIAVIT（一种天然蓝莓和沙棘提取物）是否对 2 型糖尿病肾病模型具有保护作用。糖尿病 db/db 小鼠在饮用水中给予 DIAVIT 治疗 14 周。我们评估了三个实验组（瘦+载体、db/db+载体、db/db+DIAVIT）的功能、结构和超微结构表型。我们还研究了 DIAVIT 作用机制中涉及的血管生成和纤维化途径。糖尿病 db/db 小鼠出现高血糖、蛋白尿和肾小球水通透性增加；DIAVIT 可预防后两者。db/db 小鼠出现纤维化肾小球、内皮损伤和肾小球超微结构改变，而 DIAVIT 治疗组小鼠没有这些改变。db/db 肾脏皮质中血管内皮生长因子 A（VEGF-A）剪接发生改变，增加了促血管生成的 VEGF-A165 与抗血管生成的 VEGF-A165b 的比值。DIAVIT 治疗部分阻止了这种改变。DIAVIT 中丰富的花色苷矢车菊素通过磷酸化剪接因子 SRSF6，增加了培养的足细胞中 VEGF-A165b 的表达，相对于总 VEGF-A165。DIAVIT，特别是矢车菊素，通过改变 VEGF-A 的剪接，挽救了糖尿病肾病的表型。这项研究通过基因剪接和表达的调控，强调了天然药物在糖尿病肾病治疗中的潜力。
