Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
Cell Metab. 2017 Mar 7;25(3):713-726. doi: 10.1016/j.cmet.2017.01.004. Epub 2017 Feb 9.
Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.
糖尿病肾病（DKD）是严重肾脏疾病最常见的病因，目前几乎没有能够预防肾功能进行性丧失的治疗方法。DKD 的特征是肾小球滤过率改变和蛋白尿。在 DKD 中常见的观察结果是存在肾脏脂肪变性，但这种观察结果的机制及其对疾病进展的贡献程度尚不清楚。血管内皮生长因子 B（VEGF-B）通过调节内皮脂肪酸转运来控制肌肉脂质积累。在这里，我们在 DKD 的实验小鼠模型中证明，肾脏 VEGF-B 的表达与疾病的严重程度相关。在 DKD 小鼠模型中抑制 VEGF-B 信号通路可降低肾脏脂肪毒性，使足细胞重新对胰岛素信号敏感，抑制 DKD 相关病变的发展，并防止肾功能障碍。此外，我们发现 DKD 患者的 VEGF-B 水平升高，这表明 VEGF-B 拮抗剂代表了一种治疗 DKD 的新方法。
