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      Comprehensive Proteomics Analysis Identifies CD38-Mediated NAD + Decline Orchestrating Renal Fibrosis in Pediatric Patients With Obstructive Nephropathy

      research-article
      1 , 2 , , 3 , 4 , , 5 , , 3 , 4 , , 6 , , 7 , 7 , 1 , 2 , 6 , 8 , 1 , 1 , 1 , 1 , 2 , 6 , , 3 , 4 , , 1 , 2 , 5 ,
      Molecular & Cellular Proteomics : MCP
      American Society for Biochemistry and Molecular Biology
      obstructive nephropathy, renal fibrosis, kidney proteomics, NAD+, CD38, CKD, chronic kidney disease, DIA, data-independent acquisition, FAO, fatty acid oxidation, MS, mass spectrometry, NAM, nicotinamide, PARP, poly (ADP-ribose) polymerase, ROC, receiver operating characteristic curves, SIRT, sirtuin, TGF, transforming growth factor, UPJO, ureteropelvic junction obstruction, UUO, unilateral ureteral obstruction

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          Abstract

          Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD + metabolism and NAD +-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD + levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD + supplementation significantly recovered NAD + levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD + decline as a potential therapeutic target for obstruction-induced renal fibrosis.

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          Highlights

          • Proteomics uncovered a profibrotic and inflammatory phenotype in obstructed kidneys.

          • Obstruction induced a global metabolic dysregulation and an aberrant NAD + metabolism.

          • CD38 was strongly induced in human and experimental obstructive nephropathy.

          • CD38 deletion or inhibition mitigated obstruction-induced renal fibrosis.

          In Brief

          Obstructive nephropathy is a leading cause of kidney injury in infants and children. In this work, we performed comparative proteomics of control and obstructed kidneys from human and experimental obstructive nephropathy and uncovered the aberrant NAD + metabolism, which was partially induced by CD38 upregulation. Deletion or inhibition of CD38 reduced obstruction-associated renal fibrosis and inflammation. These findings emphasized the therapeutic potential of CD38 and NAD + metabolism in obstructive nephropathy.

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          Most cited references48

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          Metascape provides a biologist-oriented resource for the analysis of systems-level datasets

          A critical component in the interpretation of systems-level studies is the inference of enriched biological pathways and protein complexes contained within OMICs datasets. Successful analysis requires the integration of a broad set of current biological databases and the application of a robust analytical pipeline to produce readily interpretable results. Metascape is a web-based portal designed to provide a comprehensive gene list annotation and analysis resource for experimental biologists. In terms of design features, Metascape combines functional enrichment, interactome analysis, gene annotation, and membership search to leverage over 40 independent knowledgebases within one integrated portal. Additionally, it facilitates comparative analyses of datasets across multiple independent and orthogonal experiments. Metascape provides a significantly simplified user experience through a one-click Express Analysis interface to generate interpretable outputs. Taken together, Metascape is an effective and efficient tool for experimental biologists to comprehensively analyze and interpret OMICs-based studies in the big data era.
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            iProX: an integrated proteome resource

            Abstract Sharing of research data in public repositories has become best practice in academia. With the accumulation of massive data, network bandwidth and storage requirements are rapidly increasing. The ProteomeXchange (PX) consortium implements a mode of centralized metadata and distributed raw data management, which promotes effective data sharing. To facilitate open access of proteome data worldwide, we have developed the integrated proteome resource iProX (http://www.iprox.org) as a public platform for collecting and sharing raw data, analysis results and metadata obtained from proteomics experiments. The iProX repository employs a web-based proteome data submission process and open sharing of mass spectrometry-based proteomics datasets. Also, it deploys extensive controlled vocabularies and ontologies to annotate proteomics datasets. Users can use a GUI to provide and access data through a fast Aspera-based transfer tool. iProX is a full member of the PX consortium; all released datasets are freely accessible to the public. iProX is based on a high availability architecture and has been deployed as part of the proteomics infrastructure of China, ensuring long-term and stable resource support. iProX will facilitate worldwide data analysis and sharing of proteomics experiments.
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              Mitochondrial energetics in the kidney

              Mitochondria provide the kidney with energy to remove waste from the blood and regulate fluid and electrolyte balance. This Review discusses how mitochondrial homeostasis is maintained, the changes in mitochondrial energetics that occur in acute kidney injury and diabetic nephropathy, and how targeting mitochondrial energetics might aid the treatment of renal disease.
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                Author and article information

                Contributors
                Journal
                Mol Cell Proteomics
                Mol Cell Proteomics
                Molecular & Cellular Proteomics : MCP
                American Society for Biochemistry and Molecular Biology
                1535-9476
                1535-9484
                17 February 2023
                March 2023
                17 February 2023
                : 22
                : 3
                : 100510
                Affiliations
                [1 ]Department of Pediatric Urology, Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
                [2 ]National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
                [3 ]Laboratory of Proteomics & Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
                [4 ]University of Chinese Academy of Sciences, Beijing, China
                [5 ]Medical School of Chinese PLA, Beijing, China
                [6 ]Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
                [7 ]Department of Dermatology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
                [8 ]College of Graduate, Hebei North University, Zhangjiakou, China
                Author notes
                []For correspondence: Huixia Zhou; Fuquan Yang; Xiubin Li klootair@ 123456163.com fqyang@ 123456ibp.ac.cn huixia99999@ 123456163.com
                [‡]

                These authors contributed equally to this work.

                Article
                S1535-9476(23)00019-1 100510
                10.1016/j.mcpro.2023.100510
                10025283
                36804530
                39406302-6798-4e7a-8426-ff5a9ca0dff9
                © 2023 The Authors

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

                History
                : 28 October 2022
                : 28 January 2023
                Categories
                Research

                Molecular biology
                obstructive nephropathy,renal fibrosis,kidney proteomics,nad+,cd38,ckd, chronic kidney disease,dia, data-independent acquisition,fao, fatty acid oxidation,ms, mass spectrometry,nam, nicotinamide,parp, poly (adp-ribose) polymerase,roc, receiver operating characteristic curves,sirt, sirtuin,tgf, transforming growth factor,upjo, ureteropelvic junction obstruction,uuo, unilateral ureteral obstruction

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