Identification and verification of vascular cell adhesion protein 1 as an immune-related hub gene associated with the tubulointerstitial injury in diabetic kidney disease.
Identification and verification of vascular cell adhesion protein 1 as an immune-related hub gene associated with the tubulointerstitial injury in diabetic kidney disease.
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血管细胞粘附蛋白1作为糖尿病肾病肾小管间质损伤免疫相关中枢基因的鉴定和验证。
DOI：
10.1080/21655979.2021.1976540
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发表时间：
2021-12
期刊：
影响因子：
4.9
通讯作者：
Xiong Z
中科院分区：
文献类型：
--
作者：
Jia Y;Xu H;Yu Q;Tan L;Xiong Z
糖尿病肾病（DKD）是慢性肾病（CKD）和终末期肾病（ESRD）的主要原因，但其发病机制尚不完全清楚。肾小管间质损伤在 DKD 的发生和发展中起着至关重要的作用。本研究旨在利用生物信息学策略研究肾小管间质免疫细胞浸润的概况，并揭示 DKD 中肾小管细胞损伤和间质炎症之间的潜在机制。首先，xCell 分析发现 DKD 肾小管间质中表现出显着变化的免疫细胞，包括上调的 CD4+ T 细胞、Th2 细胞、CD8+ T 细胞、M1 巨噬细胞、活化的树突状细胞 (DC) 和常规 DC，以及下调的 Tregs。其次，与其他形式的程序性细胞死亡相比，焦亡被认为是细胞死亡的主要形式。血管细胞粘附蛋白 1 (VCAM1) 被确定为排名最高的枢纽基因。相关性分析显示，VCAM1与肾小管间质细胞焦亡、浸润免疫细胞呈显着正相关。 DKD 肾小管间质中 VCAM1 的上调在欧洲肾 cDNA Bank 队列中得到进一步验证，并观察到与肾小球滤过率 (GFR) 呈负相关。我们的体外研究验证了糖尿病条件下 HK-2 细胞中 VCAM1 表达增加，双硫仑抑制细胞焦亡可减少 VCAM1 表达、炎症细胞因子释放和纤维化。总之，我们的研究发现肾小管细胞中 VCAM1 表达上调，这可能与浸润的免疫细胞相互作用，从而促进纤维化。 FDA 批准的药物双硫仑可能通过靶向肾小管焦亡和 VCAM1 表达来改善 DKD 的纤维化。
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), but the pathogenesis is not completely understood. Tubulointerstitial injury plays critical roles in the development and progression of DKD. The present study aimed to investigate the profile of tubulointerstitial immune cell infiltration and reveal the underlying mechanisms between tubular cell injury and interstitial inflammation in DKD using bioinformatics strategies. First, xCell analysis identified immune cells displaying significant changes in the DKD tubulointerstitium, including upregulated CD4+ T cells, Th2 cells, CD8+ T cells, M1 macrophages, activated dendritic cells (DCs) and conventional DCs, as well as downregulated Tregs. Second, pyroptosis was identified as the main form of cell death compared with other forms of programmed cell death. Vascular cell adhesion protein 1 (VCAM1) was identified as the top ranked hub gene. The correlation analysis showed that VCAM1 was significantly positively correlated with pyroptosis and infiltrated immune cells in the tubulointerstitium. Upregulation of VCAM1 in the DKD tubulointerstitium was further verified in European Renal cDNA Bank cohort and was observed to negatively correlate with the glomerular filtration rate (GFR). Our in vitro study validated increased VCAM1 expression in HK-2 cells under diabetic conditions, and pyroptosis inhibition by disulfiram decreased VCAM1 expression, inflammatory cytokine release and fibrosis. In conclusion, our study identified upregulated VCAM1 expression in renal tubular cells, which might interact with infiltrated immune cells, thus promoting fibrosis. The FDA-approved drug disulfiram might improve fibrosis in DKD by targeting tubular pyroptosis and VCAM1 expression.
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DOI：
10.1073/pnas.1415518111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Linkermann, Andreas;Skouta, Rachid;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
影响因子：
6.1
作者：
Klessens, Celine Q. F.;Zandbergen, Malu;IJpelaar, Daphne H. T.
通讯作者：
IJpelaar, Daphne H. T.
影响因子：
13.6
作者：
Evers, Beatrix D. G.;Engel, Daniel R.;Kurts, Christian
通讯作者：
Kurts, Christian
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP
影响因子：
19.6
作者：
Chow, F;Ozols, E;Tesch, GH
通讯作者：
Tesch, GH