Sirt1 inhibits renal tubular cell epithelial–mesenchymal transition through YY1 deacetylation in diabetic nephropathy

Du, Lei; Qian, Xuan; Li, Yuan; Li, Xizhi; He, Linlin; Liu, Xu; Liu, Yiqi; Li, Chengcheng; Ma, Pu; Shu, Fanglin; Lü, Qian; Yin, Xiaoxing

doi:10.1038/s41401-020-0450-2

Cited by 58 publications

(32 citation statements)

References 41 publications

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“…Glomerular hyperfiltration and proteinuria are the early clinical manifestations of DN. The pathological features of proteinuria formation are mesangial dilatation, endothelial cell degeneration and podocyte injury ( Chen et al, 2015 ; Du et al, 2021 ). Podocyte injury undergoes the processes of podocyte hypertrophy, detachment, autophagy and apoptosis, accompanied by the reduction of podocyte marker proteins (nephrin and synaptopodin).…”

Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Liu

et al. 2022

Front. Pharmacol.

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Podocytes injury is one of the leading causes of proteinuria in patients with diabetic nephropathy (DN), and is accompanied by podocytes apoptosis and the reduction of podocyte markers such as synaptopodin and nephrin. Therefore, attenuation of podocyte apoptosis is considered as an effective strategy to prevent the proteinuria in DN. In this study, we evaluated the anti-podocyte-apoptosis effect of quercetin which is a flavonol compound possessing an important role in prevention and treatment of DN and verified the effect by using db/db mice and high glucose (HG)-induced mouse podocytes (MPs). The results show that administration of quercetin attenuated the level of podocyte apoptosis by decreasing the expression of pro-apoptotic protein Bax, cleaved caspase 3 and increasing the expression of anti-apoptotic protein Bcl-2 in the db/db mice and HG-induced MPs. Furthermore, epidermal growth factor receptor (EGFR) was predicted to be the potential physiological target of quercetin by network pharmacology. In vitro and vivo experiments confirmed that quercetin inhibited activation of the EGFR signaling pathway by decreasing phosphorylation of EGFR and ERK1/2. Taken together, this study demonstrates that quercetin attenuated podocyte apoptosis through inhibiting EGFR signaling pathway, which provided a novel approach for further research of the mechanism of quercetin in the treatment of DN.

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Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Liu

et al. 2022

Front. Pharmacol.

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“…The influence of glucotoxicity on the acetylation level of intracellular proteins in key cells, including pancreatic β cells, hepatocytes, neural stem cells, and osteoclasts, is closely linked to cell function and even the occurrence and development of diseases ( Zhang et al, 2019 ; Zhou et al, 2019 ; Elumalai et al, 2020 ; Guo et al, 2021 ). Furthermore, the acetylation of DNA/RNA binding transcription factor Yin Yang 1 (YY1) in renal tubular epithelial cells under high glucose conditions has been shown to increase epithelial-mesenchymal transition (EMT) ( Du et al, 2021 ). Reductions in the acetylation of p53 may attenuate the EMT process ( Mizuguchi et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Wan

Jiang

et al. 2021

Front. Genet.

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Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.

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“…Keller et al [145], Fujimoto et al [146] and Xu et al [147] demonstrated that expression of NFATC2, PDX1 and CREB1were involved in type 2 diabetes, but these genes might be key for progression of DN. Du et al [148], Zhang et al [149] and Zhao et al [150] found that YY1, TP53 and SRF (serum-response factor) played a key role in DN through the epithelial-mesenchymal transition. Novel targets such as IL2RB, hsamir-4492, hsa-mir-4319, hsa-mir-4300, hsa-mir-3943, hsa-mir-548e-3p, hsa-mir-6077, hsa-mir-5586-5p, RET (ret proto-oncogene), MAP1LC3C, PTPRO (protein tyrosine phosphatase receptor type O), NR2C2, MAX (myc-associated factor X) and ARID3A might be responsible for progression of DN.…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in diabetic nephropathy

Joshi

Vastrad²,

Joshi

et al. 2020

Preprint

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The underlying molecular mechanisms of diabetic nephropathy (DN) have yet not been investigated clearly. In this investigation, we aimed to identify key genes involved in the pathogenesis and prognosis of DN. We selected expression profiling by high throughput sequencing dataset GSE142025 from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between DN and normal control samples were analyzed with limma package. Gene ontology (GO) and REACTOME enrichment analysis were performed using ToppGene. Then we established the protein-protein interaction (PPI) network, miRNA-DEG regulatory network and TF-DEG regulatory network. The diagnostic values of hub genes were performed through receiver operating characteristic (ROC) curve analysis. Finally, the candidate small molecules as potential drugs to treat DM were predicted using molecular docking studies. Through expression profiling by high throughput sequencing dataset, a total of 549 DEGs were detected including 275 up regulated and 274 down regulated genes. Biological process analysis of functional enrichment showed these DEGs were mainly enriched in cell activation, response to hormone, cell surface, integral component of plasma membrane, signaling receptor binding, lipid binding, immunoregulatory interactions between a lymphoid and a non-lymphoid cell and biological oxidations. DEGs with high degree of connectivity (MDFI, LCK, BTK, IRF4, PRKCB, EGR1, JUN, FOS, ALB and NR4A1) were selected as hub genes from protein-protein interaction (PPI) network, miRNA-DEG regulatory network and TF-DEG regulatory network. The ROC curve analysis confirmed that hub genes were high diagnostic values. Finally, the significant small molecules were obtained based on molecular docking studies. Our results indicated that MDFI, LCK, BTK, IRF4, PRKCB, EGR1, JUN, FOS, ALB and NR4A1 could be the potential novel biomarkers for GC diagnosis prognosis and the promising therapeutic targets. The present study may be crucial to understanding the molecular mechanism of DN initiation and progression.

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Sirt1 inhibits renal tubular cell epithelial–mesenchymal transition through YY1 deacetylation in diabetic nephropathy

Cited by 58 publications

References 41 publications

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in diabetic nephropathy

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