Identification and validation of immune-related biomarkers and potential regulators and therapeutic targets for diabetic kidney disease

Chen, Shengnan; Li, Bo; Chen, Lei; Jiang, Hongli

doi:10.1186/s12920-023-01519-6

Cited by 3 publications

(3 citation statements)

References 47 publications

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“…During AKI, the expression of the Kl gene in renal tubular cells is reduced, and its restoration can alleviate kidney damage and promote AKI recovery [26,27]. A significant decrease in GHR expression was observed in diabetic kidney disease, and GHR antagonists protected against diabetic kidney disease [28,29]. Interestingly, we observed an acute downregulation of Kl and Ghr in PTS1 and PTS2 cells, which was negatively correlated with Ezh2 expression.…”

Section: Discussionmentioning

confidence: 63%

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Zou,

Chen,

Zhou

et al. 2024

Kidney Blood Press Res

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Introduction: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and mortality. Inhibition of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) by its inhibitor 3-DZNeP (3-Deazaneplanocin A) exerts renal benefits in acute renal ischemia-reperfusion injury (IRI). However, the underlying mechanisms is not completely known. This study aimed to elucidate the pathological mechanism of EZH2 in renal IRI by combination of multi-omics analysis and expression profiling in a public clinical cohort. Methods: In this study, C57BL/6J mice were used to establish acute kidney injury model, which were treated with 3-DZNeP for 24 hours. Kidney samples were collected for RNA-seq analysis, which was combined with publicly available EZH2-ChIP-seq data of mouse embryonic stem cell for a joint analysis to identify differentially expressed genes. Several selected differentially expressed genes were verified by quantitative PCR. Finally, single-nucleus sequencing data and expression profiling in public clinical datasets were used to confirm the negative correlation of the selected genes with EZH2 expression. Results: 3-DZNeP treatment significantly improved renal pathology and function in IRI mice. Through RNA-seq analysis combined with EZH2 ChIP-seq database, 162 differentially expressed genes were found, which might be involved in EZH2-mediated pathology in IRI kidneys. Four differential expressed genes (Scd1, Cidea, Ghr, and Kl) related to lipid metabolism or cell growth were selected based on GO and KEGG enrichment analysis, which were validated by quantitative PCR. Data from snRNA-seq revealed the negative correlation of these four genes with Ezh2 expression in different subpopulations of proximal tubular cells in IRI mice in different pattern. Finally, the negative correlation of these four genes with EZH2 expression was confirmed in patients with acute kidney injury in two clinical datasets. Conclusions: Our study indicates that Scd1, Cidea, Ghr, and Kl are downstream genes regulated by EZH2 in AKI. Upregulation of EZH2 in AKI inhibits the expression of these four genes in different population of proximal tubular cells to minimize normal physiological function, and promote acute or chronic cell injuries following acute kidney injury.

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Section: Discussionmentioning

confidence: 63%

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Zou,

Chen,

Zhou

et al. 2024

Kidney Blood Press Res

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“…It is worth noting some differences found in this study compared to previous studies. 23 Differences in GLB, lymphocyte, and PLT levels between the 2 groups were not significant ( P > .05) indicating that immune factors may not be the main cause of DKD progression. Moreover, no significant difference was observed in blood ALT or LDL-C levels between the 2 groups.…”

Section: Discussionmentioning

confidence: 87%

Atherogenic Index of Plasma as an Early Marker of Chronic Kidney Disease and Liver Injury in Type 2 Diabetes

Li,

Miao,

Zhong

et al. 2024

Clin Med Insights Endocrinol Diabetes

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Background: Diabetic kidney disease (DKD) is the main cause of end-stage renal disease and has a high mortality rate. Currently, no effective treatments are available to reduce the progression of kidney damage associated with diabetes. Objectives: To explore the influence and predictive value of the atherogenic index of plasma (AIP) on early chronic kidney disease and liver injury in patients with type 2 diabetes mellitus (T2DM). Methods: Medical records of 1057 hospitalized adult patients with T2DM between January 2021 and December 2022 were collected. The predictive value of AIP, renal function, and liver injury in patients with T2DM were analyzed using Pearson’s correlation, multiple logistic regression, and receiver operating characteristic (ROC) curve analyses. Results: AIP was a sensitive indicator of early liver and kidney injury in patients with T2DM. Patients in the DKD group showed increased AIP that positively correlated with serum creatinine, uric acid, and β2-microglobulin levels. Increased AIP negatively correlated with estimated glomerular filtration rate (eGFR). AIP significantly correlated with alanine aminotransferase and aspartate aminotransferase levels and glutamyl transpeptidase-to-platelet ratio (GPR). An eGFR of 60-100 mL/min/1.73 m2 significantly increased the risk of DKD as the AIP increased. At lower GPR levels, the risk of DKD significantly increased with increasing AIP. However, no significant difference was found between the 2 groups when the GPR was >0.1407. The ROC curve analysis showed that AIP could predict early liver injury. Conclusions: AIP is directly involved in early liver and kidney injury in T2DM and may be a sensitive indicator for early detection.

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“…With the rapid development of the economy and society, the prevalence of DKD is gradually increasing worldwide which imposes a heavy economic and social burden. Our previous bioinformatics analysis found that RES can reverse gene expression abnormalities in DKD patients’ glomerulus [ 37 ]. Moreover, as a natural active ingredient, RES has the characteristics of being non-toxic and harmless [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation

Chen

et al. 2023

J Transl Med

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Background Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited. Methods Drug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins. Results After the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR. Conclusions RES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.

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Identification and validation of immune-related biomarkers and potential regulators and therapeutic targets for diabetic kidney disease

Cited by 3 publications

References 47 publications

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Atherogenic Index of Plasma as an Early Marker of Chronic Kidney Disease and Liver Injury in Type 2 Diabetes

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation

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