Modulation of transforming growth factor-β-induced kidney fibrosis by leucine-rich ⍺-2 glycoprotein-1.
Modulation of transforming growth factor-β-induced kidney fibrosis by leucine-rich ⍺-2 glycoprotein-1.
复制标题
富含亮氨酸α-2糖蛋白-1对转化生长因子-β诱导的肾纤维化的调节
DOI：
10.1016/j.kint.2021.10.023
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发表时间：
2022-03
影响因子：
19.6
通讯作者：
Lee K
中科院分区：
文献类型：
--
作者：
Hong Q;Cai H;Zhang L;Li Z;Zhong F;Ni Z;Cai G;Chen XM;He JC;Lee K
肾纤维化被认为是进展性慢性肾脏病的最终共同途径，但有效的治疗方法在临床应用中仍鲜有成功。我们最近发现，分泌型富含亮氨酸的α-2糖蛋白-1（LRG1）的表达与2型糖尿病患者肾脏预后恶化相关，且LRG1可增强内皮细胞转化生长因子-β（TGF-β）信号传导，从而促进糖尿病肾病进展。虽然LRG1表达增加在糖尿病肾脏的肾小球内皮细胞中最为显著，但在肾小管间质区也观察到其表达升高。在此，我们探究了LRG1在肾脏上皮细胞以及与糖尿病无关的TGF-β介导的肾小管间质纤维化中的潜在作用。在培养的肾脏上皮细胞中，肿瘤坏死因子-α可诱导LRG1表达，并增强TGF-β/Smad3信号转导。在单侧输尿管梗阻和马兜铃酸致纤维化模型中，小鼠全身性Lrg1缺失可显著减轻肾小管间质纤维化，同时肾小管上皮细胞中Smad3磷酸化水平降低。在肾脏上皮细胞特异性过表达LRG1的小鼠中，虽然基线时未观察到明显表型，但在梗阻肾脏中观察到肾小管间质纤维化显著加剧。这与肾脏上皮细胞和α-平滑肌肌动蛋白阳性间质细胞中Smad3磷酸化增强有关。将肾脏上皮细胞与原代肾脏成纤维细胞共培养证实，上皮来源的LRG1可增强TGF-β-1介导的肾脏成纤维细胞中Smad3的激活。因此，我们的结果表明，LRG1表达增强诱导的上皮损伤以自分泌和旁分泌方式放大TGF-β信号，促进肾小管间质纤维化。因此，以LRG1为治疗靶点可能是遏制慢性肾脏病肾纤维化进展的有效手段。
Kidney fibrosis is considered the final convergent pathway for progressive chronic kidney diseases, but there is still a paucity of success in clinical application for effective therapy. We recently demonstrated that the expression of secreted leucine-rich α-2 glycoprotein-1 (LRG1) is associated with worsened kidney outcomes in patients with type 2 diabetes and that LRG1 enhances endothelial transforming growth factor-β signaling to promote diabetic kidney disease progression. While the increased expression of LRG1 was most prominent in the glomerular endothelial cells in diabetic kidneys, its increase was also observed in the tubulointerstitial compartment. Here, we explored the potential role of LRG1 in kidney epithelial cells and TGF-β-mediated tubulointerstitial fibrosis independent of diabetes. LRG1 expression was induced by tumor necrosis factor-α in cultured kidney epithelial cells and potentiated TGF-β/Smad3 signal transduction. Global Lrg1 loss in mice led to marked attenuation of tubulointerstitial fibrosis in models of unilateral ureteral obstruction and aristolochic acid fibrosis associated with concomitant decreases in Smad3 phosphorylation in tubule epithelial cells. In mice with kidney epithelial cell-specific LRG1 overexpression, while no significant phenotypes were observed at baseline, marked exacerbation of tubulointerstitial fibrosis was observed in the obstructed kidneys. This was associated with enhanced Smad3 phosphorylation in both kidney epithelial cells and α-smooth muscle actin-positive interstitial cells. Co-culture of kidney epithelial cells with primary kidney fibroblasts confirmed the potentiation of TGF-β-1mediated Smad3 activation in kidney fibroblasts through epithelial-derived LRG1. Thus, our results indicate that enhanced LRG1 expression induced epithelial injury is an amplifier of TGF-β signaling in autocrine and paracrine manners promoting tubulointerstitial fibrosis. Hence, therapeutic targeting of LRG1 may be an effective means to curtail kidney fibrosis progression in chronic kidney disease.
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影响因子：
2.9
作者：
Furukawa, Kenta;Kawamoto, Koichi;Nagano, Hiroaki
通讯作者：
Nagano, Hiroaki
影响因子：
13.6
作者：
Hong, Quan;Zhang, Lu;Lee, Kyung
通讯作者：
Lee, Kyung
影响因子：
19.6
作者：
Lai, Han;Chen, Anqun;Lee, Kyung
通讯作者：
Lee, Kyung
DOI：
10.1038/labinvest.2014.43
发表时间：
2014-05
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Andersen JD;Boylan KL;Jemmerson R;Geller MA;Misemer B;Harrington KM;Weivoda S;Witthuhn BA;Argenta P;Vogel RI;Skubitz AP
通讯作者：
Skubitz AP