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      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

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          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.


          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).


          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.


          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).

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          Most cited references 134

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          Chronic kidney disease: effects on the cardiovascular system.

          Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.
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            GATHER: a systems approach to interpreting genomic signatures.

            Understanding the full meaning of the biology captured in molecular profiles, within the context of the entire biological system, cannot be achieved with a simple examination of the individual genes in the signature. To facilitate such an understanding, we have developed GATHER, a tool that integrates various forms of available data to elucidate biological context within molecular signatures produced from high-throughput post-genomic assays. Analyzing the Rb/E2F tumor suppressor pathway, we show that GATHER identifies critical features of the pathway. We further show that GATHER identifies common biology in a series of otherwise unrelated gene expression signatures that each predict breast cancer outcome. We quantify the performance of GATHER and find that it successfully predicts 90% of the functions over a broad range of gene groups. We believe that GATHER provides an essential tool for extracting the full value from molecular signatures generated from genome-scale analyses. GATHER is available at http://gather.genome.duke.edu/
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              The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.

              Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration.

                Author and article information

                Redox Biol
                Redox Biol
                Redox Biology
                20 February 2020
                July 2020
                20 February 2020
                : 34
                [a ]Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
                [b ]Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China
                [c ]Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
                [d ]Rutgers University, New Brunswick, NJ, 08901, USA
                [e ]Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
                [f ]Division of Vascular and Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
                [g ]Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
                [h ]Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
                [i ]School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA
                [j ]Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
                Author notes
                []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. xfyang@ 123456temple.edu
                S2213-2317(19)31550-2 101460
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Articles from the Special Issue on Redox Signalling and Cardiovascular Disease; Edited by Christopher Kevil and Yabing Chen


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