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Zhang R , Saredy J , Shao Y , Yao T , Liu L , Saaoud F , Yang WY , Sun Y , Johnson C , Drummer Cth , Fu H , Lu Y , Xu K , Liu M , Wang J , Cutler E , Yu D , Jiang X , Li Y , Li R , Wang L , Choi ET , Wang H , Yang X
End-stage renal disease is different from chronic kidney disease in upregulating ROS-modulated proinflammatory secretome in PBMCs - A novel multiple-hit model for disease progression
Redox Biol. 2020 Jul;34 :101460
PMID: 32179051    PMCID: PMC7327976    URL: https://www.ncbi.nlm.nih.gov/pubmed/32179051
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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).
2213-2317 Zhang, Ruijing Saredy, Jason Shao, Ying Yao, Tian Liu, Lu Saaoud, Fatma Yang, William Y Sun, Yu Johnson, Candice Drummer, Charles 4th Fu, Hangfei Lu, Yifan Xu, Keman Liu, Ming Wang, Jirong Cutler, Elizabeth Yu, Daohai Jiang, Xiaohua Li, Yafeng Li, Rongshan Wang, Lihua Choi, Eric T Wang, Hong Yang, Xiaofeng R01 DK104116/DK/NIDDK NIH HHS/United States R01 DK113775/DK/NIDDK NIH HHS/United States R01 HL131460/HL/NHLBI NIH HHS/United States R01 HL147565/HL/NHLBI NIH HHS/United States Journal Article Redox Biol. 2020 Jul;34:101460. doi: 10.1016/j.redox.2020.101460. Epub 2020 Feb 20.