Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling

Liu, Min; Liang, Kai‐Li; Zhen, Junhui; Zhou, Meng; Wang, Xiaojie; Wang, Ziying; Wei, Xinbing; Zhang, Yan; Sun, Yu; Zhou, Zhuanli; Su, Hua; Zhang, Chun; Li, Ningjun; Gao, Chengjiang; Peng, Jun; Yi, Fan

doi:10.1038/s41467-017-00498-4

Cited by 251 publications

(217 citation statements)

References 51 publications

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“…Currently, It is widely accepted that podocyte damage is not only associated with the degree of proteinuria, but also correlates with glomerulosclerosis development and renal function decline [2,3]. Podocyte damage is one of the early-stage events in many human kidney diseases, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), membranous nephropathy (MN), lupus nephritis (LN) and other CKDs [4,5].…”

Section: Introductionmentioning

confidence: 99%

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Zuo

Shen

Pan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Podocyte damage is associated with proteinuria, glomerulosclerosis and decline of renal function. This study aimed to screen critical genes associated with podocyte injury in chronic kidney disease (CKD) by weighted gene correlation network analysis (WGCNA), and explore related functions. Methods: GSE66107, GSE93798, GSE30528, GSE32591 gene expression data including podocyte injury models or glomeruli in CKD patients were downloaded from the GEO database. R was used for data analysis. Differentially expressed genes (DEGs) (FDR< 0.05 or |Fold Change|≥1.5) in GSE993395 were assessed by WGCNA. According to Gene Ontology (GO) and known podocyte standard genes (PSGs), podocyte injury-associated modules were defined, with hub genes selected based on average intramodular connectivity. The Cytoscape software was used for network visualization. Nephroseq was used to assess the clinical significance of hub genes. Small interfering RNA (siRNA) was used to evaluate the roles of hub genes in podocyte injury Results: Totally 7957 DEGs were screened, with 15 (co.DEGs) altered in all 4 datasets; 4031 DEGs were used for WGCNA, encompassing 12 modules. Green modules (most PSGs and co.DEGs) were significantly enriched in glomerular development, and considered podocyte injury-associated modules. Furthermore, MAGI2 (a hub gene) was also a co.DEG and PSG. Glomerular MAGI2 levels were reduced in various kidney diseases, and positively and negatively associated with glomerular filtration rate and urinary protein levels in CKD patients. Moreover, MAIG2 knockdown reduced NPHS2, CD2AP and SYNPO levels, and induced podocyte rearrangement and apoptosis. Conclusion: MAGI2 identified by WGCNA regulates cytoskeletal rearrangement in podocytes, with its loss predisposing to proteinuria and CKD.

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Section: Introductionmentioning

confidence: 99%

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Zuo

Shen

Pan

et al. 2018

Cell Physiol Biochem

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“…The application of MS-275, a selective inhibitor of HDAC1 over HDAC3 and with no inhibitory activity towards HDAC8 effectively inhibits TGF-β signaling in renal interstitial fibroblasts. The treatment completely abolishes the expression of TGF-β receptor I and the phosphorylation of SMAD3, which suggests the efficient regulatory mechanism in several ways in fibrotic kidney diseases (33).…”

Section: Tgf-β Signaling Pathwaymentioning

confidence: 87%

Exploring the sirtuin functionality in aging through the human protein interaction networks

Nahálková¹

2019

Preprint

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The sirtuin family contains seven proteins with the functions in multiple diseases of aging, which makes them an attractive subject for the development of therapies of age-related diseases and anti-aging treatments. The primary objective of the protein-interaction network analysis presented here is to identify the signaling pathways and protein nodes driving the functions of the sirtuins. For this purpose, the protein-protein interaction data were collected from the available public databases, which fulfilled the quality threshold and included at least one member of the sirtuin family. The databases provided 66 interactions validated by several experiments, which were further processed by the bioinformatic tools connected to the integrated genomic, proteomic, and pharmacologic data. The interactions were analyzed by the pathway enrichment, the gene function prediction analysis, and the protein node prioritization by use of Cytoscape applications GeneMania and Cytohubba. The constructed sirtuin protein interaction network (SPIN) contained after the extension 98 protein nodes. TGFβ, PTK2, CARM1, Notch signaling and the pathways regulating androgen and estrogen levels, significantly scored in the pathway enrichment analysis of SPIN. The enriched signaling pathways mediating the pleiotropic effects of the sirtuin family, play the roles in several age-related diseases probably. The Cytohubba application has highlighted the function of HDAC1, EP300, SMAD4, MYC, SIN3A, RBBP4, HDAC, SIN3B, RBBP7 and SMAD3 as the high priority protein nodes driving the molecular functions of SPIN. The presented protein interaction study provide new understandings of the sirtuin functions in the longevity and diseases of aging including cancer, neurodegenerative and metabolic disorders.

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“…Several studies have implied that the anomalous expression of nephrin, podocin and integrin a3b1 in podocytes would destroy the cells' normal structure and adhesive function, causing podocyte loss and apoptosis, which are closely related to the incidence of DN. Once podocyte damage occurs, the normal structure of foot processes is destroyed and the function is disordered, causing further podocyte injury and apoptosis, which are likely to lead to proteinuria, thus further promoting the development of renal functional injury and finally accelerating the DN progression 22 . In the present study, we found that the injection of STZ combined with a high-glucose/high-fat diet could significantly increase the FBG, promoting diabetic progression and further affecting renal function.…”

Section: Discussionmentioning

confidence: 99%

Berberine ameliorates renal impairment and inhibits podocyte dysfunction by targeting the phosphatidylinositol 3‐kinase–protein kinase B pathway in diabetic rats

Zhou

Ding

et al. 2019

J of Diabetes Invest

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Aims/Introduction Amelioration of renal impairment is the key to diabetic nephropathy (DN) therapy. The progression of DN is closely related to podocyte dysfunction, but the detailed mechanism has not yet been clarified. The present study aimed to explore the renal impairment amelioration effect of berberine and related mechanisms targeting podocyte dysfunction under the diabetic state. Materials and Methods Streptozotocin (35 mg/kg) was used to develop a DN rat model together with a high‐glucose/high‐lipid diet. Renal functional parameters and glomerular ultrastructure changes were recorded. The alterations of phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt) and phosphorylated Akt in the kidney cortex were determined by western blot. Meanwhile, podocyte dysfunction was induced and treated with berberine and LY294002. After that, podocyte adhesion functional parameters, protein biomarker and the alterations of the PI3K–Akt pathway were detected. Results Berberine reduces the increased levels of biochemical indicators, and significantly improves the abnormal expression of PI3K, Akt and phosphorylated Akt in a rat kidney model. In vitro, a costimulating factor could obviously reduce the podocyte adhesion activity, including decreased expression of nephrin, podocin and adhesion molecule α3β1 levels, to induce podocyte dysfunction, and the trends were markedly reversed by berberine and LY294002 therapy. Furthermore, reduction of PI3K and phosphorylated Akt levels were observed in the berberine (30 and 60 μmol/L) and LY294002 (40 μmol/L) treatment group, but the Akt protein expression showed little change. Conclusions Berberine could be a promising antidiabetic nephropathy drug through ameliorating renal impairment and inhibiting podocyte dysfunction in diabetic rats, and the underlying molecular mechanisms might be involved in the regulation of the PI3K–Akt signaling pathway.

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Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling

Cited by 251 publications

References 51 publications

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

Exploring the sirtuin functionality in aging through the human protein interaction networks

Berberine ameliorates renal impairment and inhibits podocyte dysfunction by targeting the phosphatidylinositol 3‐kinase–protein kinase B pathway in diabetic rats

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