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
Ruijing Zhang,
Jason Saredy,
Ying Shao,
Tian Yao,
Lu Liu,
Fatma Saaoud,
William Y. Yang,
Yu Sun,
Candice Johnson,
Charles Drummer, IV,
Hangfei Fu,
Yifan Lu,
Keman Xu,
Ming Liu,
Jirong Wang,
Elizabeth Cutler,
Daohai Yu,
Xiaohua Jiang,
Yafeng Li,
Rongshan Li,
Lihua Wang,
Eric T. Choi,
Hong Wang,
Xiaofeng Yang
Affiliations
Ruijing Zhang
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China; Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
Jason Saredy
Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Ying Shao
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Tian Yao
Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
Lu Liu
Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Fatma Saaoud
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
William Y. Yang
Rutgers University, New Brunswick, NJ, 08901, USA
Yu Sun
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Candice Johnson
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Charles Drummer, IV
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Hangfei Fu
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Yifan Lu
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Keman Xu
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Ming Liu
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
Jirong Wang
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Elizabeth Cutler
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA
Daohai Yu
Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Xiaohua Jiang
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Yafeng Li
Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
Rongshan Li
Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
Lihua Wang
Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China
Eric T. Choi
Division of Vascular and Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Hong Wang
Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Xiaofeng Yang
Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Corresponding author. Centers for Inflammation, Translational & Clinical Lung Research, Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
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).
