Background

The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined.

Methods

We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG).

Results

1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1β and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-β1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent.

Conclusions

Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).

中文翻译：

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终末期肾病与慢性肾病的不同之处在于，PBMC 中 ROS 调节的促炎分泌组上调，这是一种新型的疾病进展多重打击模型。

背景

慢性肾病（CKD）向终末期肾病（ESRD）转变以及 CKD 加速心血管和其他组织炎症的分子机制仍不清楚。

方法

我们对来自 NCBI-GEO 数据库的 CKD 和 ESRD 患者外周血单核细胞 (PBMC) 的 7 个微阵列数据集进行了全面的数据分析，其中我们检查了 2641 个分泌组基因 ( SG ) 的表达。

结果

1) 86.7%的中产阶级（分子量>500道尔顿）尿毒症毒素（UTs）由SGs编码；2） ESRD患者PBMCs中SGs的上调（121个SGs）显着高于CKD患者（44个SGs）；3） PBMC分泌组的转录组分析比传统分泌组分析具有识别更全面的分泌组的优势；4） ESRD诱导的SG具有很强的促炎途径；5)基于促炎细胞因子的 UT（例如 IL-1β 和 IL-18）促进 SG 的 ESRD 调节；6) ESRD上调的共刺激受体CD48和CD58增加了PBMC中的分泌上调，并且在组织中被极大地放大；7）M1 和 M2 巨噬细胞极化信号导致 ESRD 和 CKD 上调 SG；8) ESRD 和 CKD 上调的 SG 含有通过上调促炎性 IGFBP7 和下调抗炎性 TGF-β1 和端粒稳定剂 SERPINE1/PAI-1 促进衰老的调节因子；9） ROS途径在介导ESRD上调的SGs（11.6％）中比在CKD上调的SGs（6.8％）中发挥更大的作用，并且ESRD上调的SGs中有一半是ROS独立的。

结论

我们的分析表明，CKD 和 ESRD 患者的 PBMC 中出现新的分泌细胞上调，与尿毒症毒素协同作用，促进炎症和潜在的疾病进展。我们的研究结果为 PBMC 分泌组上调促进疾病进展提供了新的见解，并可能为 CKD、ESRD 及其加速的心血管疾病、其他炎症和癌症的新治疗方案确定新的治疗靶点。（总字数：279）。