Abstract：
Transforming growth factor (TGF)-β signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-β signaling regulators can substantially influence TGF-β\'s effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-β-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-β-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-β signaling to attenuate DKD.
摘要：
TGF-β信号传导是一种公认的DKD致病介质。然而,由于其多效作用，它的全身阻滞在治疗上不是最佳的。TGF-β信号调节因子的表达可以以细胞或环境特异性方式显著影响TGF-β的作用。其中,富含亮氨酸的α2-糖蛋白1（LRG1）在DKD的肾小球内皮细胞（GECs）中显着增加。由于LRG1是一种分泌分子，可以发挥自分泌和旁分泌作用，我们通过单细胞转录组学分析研究了糖尿病OVE26小鼠肾细胞中LRG1缺失的影响.基因表达分析证实了Lrg1在GECs中的主要表达，在糖尿病肾脏中进一步增加。Lrg1的缺失导致GECs中血管生成和TGF-β诱导的基因表达的逆转，与DKD衰减有关。值得注意的是,Lrg1丢失也减轻了糖尿病小鼠足细胞和系膜细胞中TGF-β介导的基因表达增加，表明GEC衍生的LRG1以自分泌和旁分泌方式增强肾小球细胞中的TGF-β信号传导。的确,在LRG1缺失的OVE26小鼠的肾小球细胞中观察到磷酸-Smad蛋白显著减少.这些结果表明，LRG1的特异性拮抗可能是抑制过度活跃的肾小球TGF-β信号传导以减弱DKD的有效方法。
