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 in GECs, which further increased in diabetic kidneys. Loss of led to the reversal of angiogenic and TGF-β-induced gene expression in GECs, which were associated with DKD attenuation. Notably, 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.

中文翻译：

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LRG1 缺失可有效抑制肾小球 TGF-β 信号传导，从而减轻糖尿病肾病


转化生长因子 (TGF)-β 信号传导是糖尿病肾病 (DKD) 的公认致病介质。然而，由于其多效性作用，其全身阻断在治疗上并不是最佳的。 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着影响 TGF-β 的作用。其中，DKD 患者肾小球内皮细胞 (GEC) 中富含亮氨酸的 α2-糖蛋白 1 (LRG1) 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，因此我们通过单细胞转录组分析检查了糖尿病OVE26小鼠肾细胞中LRG1缺失的影响。基因表达分析证实了 GEC 中的主要表达，并且在糖尿病肾脏中进一步增加。的缺失导致 GEC 中血管生成和 TGF-β 诱导的基因表达逆转，这与 DKD 减弱有关。值得注意的是，损失还减轻了糖尿病小鼠足细胞和系膜细胞中 TGF-β 介导的基因表达的增加，表明 GEC 衍生的 LRG1 以自分泌和旁分泌方式增强了肾小球细胞中的 TGF-β 信号传导。事实上，在 LRG1 缺失的 OVE26 小鼠肾小球细胞中观察到磷酸化 Smad 蛋白显着减少。这些结果表明，LRG1 的特异性拮抗作用可能是抑制肾小球 TGF-β 信号过度活跃以减轻 DKD 的有效方法。