LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β-Induced Angiogenesis
LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β-Induced Angiogenesis
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DOI：
10.1681/asn.2018060599
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发表时间：
2019-04-01
影响因子：
13.6
通讯作者：
Lee, Kyung
中科院分区：
文献类型：
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作者：
Hong, Quan;Zhang, Lu;Lee, Kyung
糖尿病肾病（DKD）的发病机制与肾小球内皮功能障碍和新生血管形成有关。然而，在DKD的早期阶段促成这些过程的特定分子途径尚不清楚。我们最近对肾小球内皮细胞的转录组学分析确定了一些在糖尿病小鼠中上调的促血管生成基因，包括富含亮氨酸的α-2-糖蛋白1（LRG 1）。LRG 1先前显示通过增强内皮TGF-β/激活素受体样激酶1（ALK 1）信号传导促进眼部疾病小鼠模型中的新血管形成。然而，LRG 1在肾脏中的作用，特别是在设置的DKD，一直不清楚。方法我们分析了LRG 1 mRNA在肾小球中的表达，糖尿病肾病和评估其本地化的RNA原位杂交。我们检测了单侧肾切除、链脲佐菌素诱导的糖尿病小鼠在糖尿病诱导后12周和20周Lrg 1基因切除对DKD进展的影响。我们还评估了血浆LRG 1是否与2型糖尿病患者的肾脏结局相关。结果LRG 1主要定位于肾小球内皮细胞，其表达在糖尿病肾脏中升高。LRG 1消融显著减弱糖尿病诱导的肾小球血管生成、足细胞损失和糖尿病肾小球病的发展。这些改善与糖尿病小鼠肾小球中ALK 1-Smad 1/5/8活化减少相关。此外，血浆LRG 1增加与2型糖尿病患者肾脏预后不良相关。结论这些研究结果确定LRG 1作为一种潜在的新的致病介质的糖尿病肾小球新生血管和DKD进展的危险因素。
Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich alpha-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-beta/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.