The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response

Tang, Hanfen; Yang, Ming; Liu, Yanping; Liu, Hong; Sun, Lirong; Song, Panai

doi:10.3389/fphys.2021.782677

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…Analysis of marker genes associated with the hypoxic response and kidney injury affirmed and extended our initial findings (Figure 2C). For example, injury and repair associated genes like GDF15 ( 50 ), TGFB1 ( 51 ), JUN ( 52 ), C-X-C motif chemokine ligand 1 ( CXCL1 ) ( 53 ), snail family transcriptional repressor 1 ( SNAI1 ) ( 54 ) and SOX9 ( 13, 55 ) were higher in the d20h group compared to control (Figure 2C). Hypoxia can cause cell cycle arrest through the induction of cell cycle inhibitors like CDKN1A ( 40, 56 ).…”

Section: Resultsmentioning

confidence: 99%

Hypoxic injury triggers maladaptive repair in human kidney organoids

Nunez-Nescolarde,

Piran,

Perlaza-Jiménez

et al. 2023

Preprint

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Acute kidney injury (AKI) is a common clinical disorder linked to high rates of illness and death. Ischemia is a leading cause of AKI, which can result in chronic kidney disease (CKD) through a maladaptive repair process characterised by failed epithelial regeneration, inflammation, and metabolic dysregulation. No targeted therapies exist to prevent the AKI to CKD transition and insight into ischemic AKI and maladaptive repair in humans remains limited. In this study, we report that human kidney organoids recapitulate select molecular and metabolic signatures of AKI and maladaptive repair in response to hypoxic injury. Transcriptional, proteomic, and metabolomic profiling revealed signatures of tubular injury, cell death, cell cycle arrest and altered metabolism in kidney organoids cultured in hypoxic conditions. After recovery in normoxic conditions, injured organoids displayed increased signatures associated with maladaptive repair like TNF, NF-κB, and JAK-STAT pathways, and S100A8/9. Single cell RNA sequencing localised biomarkers of AKI and maladaptive repair such as GDF15, MMP7, ICAM1, TGFB1, SPP1, C3 and CCN1 to injured proximal and distal tubules. Metabolic phenotypes linked to CKD were also evident including dysregulated glycolysis and gluconeogenesis, amino acid, bicarbonate and lipid metabolism, and elevated ceramide levels. Our multi-omic analysis provides compelling evidence for the use of kidney organoids as a model of human ischemic AKI and maladaptive repair, highlighting new and conserved biomarkers and mechanisms, and opportunities for drug screening.SummaryHuman kidney organoids recapitulate molecular and metabolic signatures of ischemic acute kidney injury and maladaptive repair, providing new insight into human disease mechanisms and opportunities for drug development.

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Section: Resultsmentioning

confidence: 99%

Hypoxic injury triggers maladaptive repair in human kidney organoids

Nunez-Nescolarde,

Piran,

Perlaza-Jiménez

et al. 2023

Preprint

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“…[697], IL18 [698], CYGB (cytoglobin) [636], EGF (epidermal growth factor) [699], TRPM2 [700], BANK1 [701], SORT1 [643], HSPG2 [645], NOX4 [702], MYH9 [703], TRPV4 [704], B4GALNT1 [705], LAG3 [706], CACNA1C [654], LRP5 [707], PIM1 [658], MDK (midkine) [708], CA2 [709], TRPC6 [710], CYP2D6 [711] and STAT4 [712] might be a biological target of type 1 diabetes mellitus. CCK (cholecystokinin) [713], IL33 [714], IRF4 [715], CXCL8 [716], MMP3 [717], DDIT4L [718], KL (klotho) [719], CXCL6 [87], CXCL1 [720], STC1 [721], PDK4 [722], RAB27B [723], CXCL5 [724], GPRC5A [725], TXNIP (thioredoxin interacting protein) [726], RAB3B [727], HSPA5 [728], DKK1 [93], NAMPT (nicotinamidephosphoribosyltransferase) [729], TNFAIP3 [730], GHR (growth hormone receptor) [731], ANXA1 [732], CD40 [733], KITLG (KIT ligand) [734], SMURF2 [735], NRG1 [684], GCLC (glutamate-cysteine ligase catalytic subunit) [685], NPHP1 [736], EPOR (erythropoietin receptor) [737], ADK (adenosine kinase) [738], SAA1…”

Section: Discussionmentioning

confidence: 99%

Screening and identification of key biomarkers in diabetic kidney disease and its complications: Evidence from bioinformatics and next generation sequencing data analysis

Vastrad¹,

Vastrad²

2023

Preprint

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Diabetic patients are prone to diabetic kidney disease (DKD), which may cause cardiovascular damage, hypertension and obesity, and reduce quality of life. As a result, the life quality of patients was seriously reduced. However, the pathogenesis of diabetic kidney disease (DKD) has not been fully elucidated, and current treatments remain inadequate. Therefore, it is essential to explore the molecular mechanism of DKD and its complications. Next Generation Sequancing (GSE217709) dataset was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were picked out by R software. Then Gene ontology (GO) and REACTOME pathway enrichment analysis were performed by g:Profiler database, protein-protein interaction (PPI) of DEGs was constructed by Human Integrated Protein-Protein Interaction rEference (HIPPIE) database . Module analysis was carried out by Cytoscape plug-in PEWCC. Subsequently, miRNA-hub gene regulatory network and TF- hub gene regulatory network were performed by miRNet database and NetworkAnalyst database. Finally, validation of hub genes was performed by receiver operating characteristic (ROC) curve analysis to predict the diagnostic effectiveness of the hub genes. In total, 958 DEGs, including 479 up regulated and 479 down regulated genes, were identified. The GO and pathway enrichment changes of DEGs were mainly enriched in biological regulation, multicellular organismal process, signaling by GPCR and extracellular matrix organization. Ten hub genes (HSPA8, HSP90AA1, HSPA5, SDCBP, HSP90B1, VCAM1, MYH9, FLNA, MDFI and PML) associated with DKD and its complications were identified. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of DKD and its complications. The identified hub genes may participate in the onset and development of DKD and its complications and serve as therapeutic targets.

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“…Furthermore, Tang et al. showed that in diabetic mice and DN patients, the expression level of CXCR2 was increased; when the CXCR1/CXCR2 axis was blocked, the renal inflammation and pathological damage in the kidneys of db/db mice could be relieved [ 35 ]. Dual specificity phosphatase 1 (DUSP1) is also known as mitogen‐activated protein kinase phosphatase 1 (MKP1).…”

Section: Discussionmentioning

confidence: 99%

Identification of key immune‐related genes and immune infiltration in diabetic nephropathy based on machine learning algorithms

Sun

Dai

2023

IET Systems Biology

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Background Diabetic nephropathy (DN) is a complication of diabetes. This study aimed to identify potential diagnostic markers of DN and explore the significance of immune cell infiltration in this pathology. Methods The GSE30528, GSE96804, and GSE1009 datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by merging the GSE30528 and GSE96804 datasets. Enrichment analyses of the DEGs were performed. A LASSO regression model, support vector machine recursive feature elimination analysis and random forest analysis methods were performed to identify candidate biomarkers. The CIBERSORT algorithm was utilised to compare immune infiltration between DN and normal controls. Results In total, 115 DEGs were obtained. The enrichment analysis showed that the DEGs were prominent in immune and inflammatory responses. The DEGs were closely related to kidney disease, urinary system disease, kidney cancer etc. CXCR2, DUSP1, and LPL were recognised as diagnostic markers of DN. The immune cell infiltration analysis indicated that DN patients contained a higher ratio of memory B cells, gamma delta T cells, M1 macrophages, M2 macrophages etc. cells than normal people. Conclusion Immune cell infiltration is important for the occurrence of DN. CXCR2, DUSP1, and LPL may become novel diagnostic markers of DN.

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The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response

Cited by 14 publications

References 22 publications

Hypoxic injury triggers maladaptive repair in human kidney organoids

Hypoxic injury triggers maladaptive repair in human kidney organoids

Screening and identification of key biomarkers in diabetic kidney disease and its complications: Evidence from bioinformatics and next generation sequencing data analysis

Identification of key immune‐related genes and immune infiltration in diabetic nephropathy based on machine learning algorithms

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