A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84 %) and Type 1 diabetes (16 %), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyzes in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.

中文翻译：

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脂肪-肾轴中的血管内皮生长因子 B 介导的脂肪酸通量导致糖尿病肾病的脂毒性。


糖尿病肾病的一个常见观察结果是脂质积累，但这种病理的机制尚不清楚。在实验模型中，抑制血管内皮生长因子 B （VEGF-B） 信号传导可预防肾小球脂质积聚并改善糖尿病肾病。在这里，我们检查了 2 型 （84%） 和 1 型 （16%） 患者的肾活检，并结合糖尿病肾病患者的 RNA-seq 数据集分析的数据挖掘。在肾小球中，系膜细胞来源的 VEGF-B 表达增加，肾小球脂质积累与肾功能受损呈正相关。肾小管脂质积累也与肾功能不全有关，但与肾小管来源的 VEGF-B 表达无关。在体外，对脂肪酸类似物 BODIPY-FA 的摄取进行了定量。VEGF-B 处理增加了内皮细胞中 BODIPY-FA 的摄取，而与针对 VEGF-B 及其受体 VEGFR1 的中和抗体预孵育消除了这种摄取。糖尿病猕猴肾脏和白色脂肪组织的转录组分析显示，VEGF-B 在白色脂肪组织中的表达高于肾脏，并且 VEGF-B 在糖尿病肾病患者的白色脂肪组织中的表达增加。糖尿病转基因小鼠的分析表明，脂肪细胞中 VEGF-B 的表达决定了脂肪分解活性、血脂异常、肾脂质积累和糖尿病肾病的发展。总体而言，VEGF-B 通过控制白脂肪组织脂肪分解以及肾小球中内皮脂肪酸的转运，是糖尿病肾病中肾脂毒性的调节剂。 我们的数据表明，肾脂质积累和 VEGF-B 表达的评估可以作为早期糖尿病肾病的生物标志物。