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      Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury

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          Abstract

          Acute kidney injury (AKI) is a severe and frequently observed condition associated with high morbidity and mortality. The molecular mechanisms underlying AKI have not been elucidated due to the complexity of the pathophysiological processes. Thus, we investigated the key biological molecules contributing to AKI based on the transcriptome profile. We analyzed the RNA sequencing data from 39 native human renal biopsy samples and 9 reference nephrectomies from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and Gene Ontology (GO) analysis revealed that various GO terms were dysregulated in AKI. Gene set enrichment analysis (GSEA) highlighted dysregulated pathways, including “DNA replication,” “chemokine signaling pathway,” and “metabolic pathways.” Furthermore, the protein-to-protein interaction (PPI) networks of the DEGs were constructed, and the hub genes were identified using Cytoscape. Moreover, weighted gene co-expression network analysis (WGCNA) was performed to validate the DEGs in AKI-related modules. Subsequently, the upregulated hub genes STUB1, SOCS1, and VHL were validated as upregulated in human AKI and a mouse cisplatin-induced AKI model. Moreover, the biological functions of STUB1 were investigated in renal tubular epithelial cells. Cisplatin treatment increased STUB1 expression in a dose-dependent manner at both the mRNA and protein levels. Knockdown of STUB1 by siRNA increased the expression of proapoptotic Bax and cleaved caspase-3 while decreasing antiapoptotic Bcl-2. In addition, silencing STUB1 increased the apoptosis of HK-2 cells and the proinflammatory cytokine production of IL6, TNFα, and IL1β induced by cisplatin. These results indicated that STUB1 may contribute to the initiation and progression of AKI by inducing renal tubular epithelial cell apoptosis and renal inflammation.

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          Most cited references37

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          KDIGO Clinical Practice Guidelines for Acute Kidney Injury

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            Incidence and outcomes in acute kidney injury: a comprehensive population-based study.

            Epidemiological studies of acute kidney injury (AKI) and acute-on-chronic renal failure (ACRF) are surprisingly sparse and confounded by differences in definition. Reported incidences vary, with few studies being population-based. Given this and our aging population, the incidence of AKI may be much higher than currently thought. We tested the hypothesis that the incidence is higher by including all patients with AKI (in a geographical population base of 523,390) regardless of whether they required renal replacement therapy irrespective of the hospital setting in which they were treated. We also tested the hypothesis that the Risk, Injury, Failure, Loss, and End-Stage Kidney (RIFLE) classification predicts outcomes. We identified all patients with serum creatinine concentrations > or =150 micromol/L (male) or > or =130 micromol/L (female) over a 6-mo period in 2003. Clinical outcomes were obtained from each patient's case records. The incidences of AKI and ACRF were 1811 and 336 per million population, respectively. Median age was 76 yr for AKI and 80.5 yr for ACRF. Sepsis was a precipitating factor in 47% of patients. The RIFLE classification was useful for predicting full recovery of renal function (P < 0.001), renal replacement therapy requirement (P < 0.001), length of hospital stay [excluding those who died during admission (P < 0.001)], and in-hospital mortality (P = 0.035). RIFLE did not predict mortality at 90 d or 6 mo. Thus the incidence of AKI is much higher than previously thought, with implications for service planning and providing information to colleagues about methods to prevent deterioration of renal function. The RIFLE classification is useful for identifying patients at greatest risk of adverse short-term outcomes.
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              Regulated cell death in AKI.

              AKI is pathologically characterized by sublethal and lethal damage of renal tubules. Under these conditions, renal tubular cell death may occur by regulated necrosis (RN) or apoptosis. In the last two decades, tubular apoptosis has been shown in preclinical models and some clinical samples from patients with AKI. Mechanistically, apoptotic cell death in AKI may result from well described extrinsic and intrinsic pathways as well as ER stress. Central converging nodes of these pathways are mitochondria, which become fragmented and sensitized to membrane permeabilization in response to cellular stress, resulting in the release of cell death-inducing factors. Whereas apoptosis is known to be regulated, tubular necrosis was thought to occur by accident until recent work unveiled several RN subroutines, most prominently receptor-interacting protein kinase-dependent necroptosis and RN induced by mitochondrial permeability transition. Additionally, other cell death pathways, like pyroptosis and ferroptosis, may also be of pathophysiologic relevance in AKI. Combination therapy targeting multiple cell-death pathways may, therefore, provide maximal therapeutic benefits.
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                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                28 June 2021
                2021
                : 8
                : 655361
                Affiliations
                [ 1 ]Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Shanghai, China
                [ 2 ]Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
                [ 3 ]Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
                Author notes

                Edited by: Kamran Ghaedi, University of Isfahan, Iran

                Reviewed by: Vicente de Paulo Martins, University of Brasilia, Brazil

                Fariba Dehghanian, University of Isfahan, Iran

                *Correspondence: Jie Teng, teng.jie@ 123456zsxmhospital.com
                [†]

                These authors have contributed equally to this work and share first authorship

                This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences

                Article
                655361
                10.3389/fmolb.2021.655361
                8273177
                34262937
                4855a195-3d56-4cf6-8465-fd86cf69de3f
                Copyright © 2021 Shi, Chen and Teng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 January 2021
                : 07 June 2021
                Categories
                Molecular Biosciences
                Original Research

                acute kidney injury,cisplatin,stub1,rna sequencing,network-based expression analysis

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