Epigenetic Regulations in Diabetic Nephropathy

Lu, Zeyuan; Liu, Na; Feng, Wenquan

doi:10.1155/2017/7805058

Cited by 63 publications

(47 citation statements)

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“…Ethnicity and differences in inherited genetics have been proposed as responses to the damage in both kidneys and heart due to diabetes (34,60). The molecular basis underlying these complications remains unknown (34). Recent evidence has suggested important roles of epigenetics leading to DN and DCM.…”

Section: Introductionmentioning

confidence: 99%

ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications

Thomas

Feng

Chakrabarti

2018

American Journal of Physiology-Endocrinology and Metabolism

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noncoding RNAs (lncRNAs) have gained widespread interest due to their prevailing presence in various diseases. lncRNA ANRIL (a. k. a. CDKN2B-AS1) is located on human chromosome 9 (p21.3) and transcribed in opposite direction to the INK4b-ARF-INK4a gene cluster. It has been identified as a highly susceptible region for diseases such as coronary artery diseases and type 2 diabetes. Here, we explored its regulatory role in diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM) in association with epigenetic modifiers p300 and polycomb repressive complex 2 (PRC2) complex. We used an ANRIL-knockout (ANRILKO) mouse model for this study. The wild-type and ANRILKO animals with or without streptozotocin-induced diabetes were monitored for 2 min. At the end of the time point, urine and tissues were collected. The tissues were measured for fibronectin (FN), type IV collagen (Col1α4), and VEGF mRNA and protein expressions. Renal function was determined by the measurement of 24-h urine volume and albumin/creatinine ratio at euthanasia. Renal and cardiac structures were investigated using periodic acid-Schiff stain and/or immunohistochemical analysis. Elevated expressions of extracellular matrix (ECM) proteins were prevented in ANRILKO diabetic animals. Furthermore, ANRILKO had a protective effect on diabetic mouse kidneys, as evidenced by lowering of urine volume and urine albumin levels in comparison with the wild-type diabetic animals. These alterations regulated by ANRIL may be mediated by p300 and enhancer of zeste 2 (EZH2) of the PRC2 complex. Our study concludes that ANRIL regulates functional and structural alterations in the kidneys and hearts in diabetes through controlling the expressions of ECM proteins and VEGF.

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Section: Introductionmentioning

confidence: 99%

ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications

Thomas

Feng

Chakrabarti

2018

American Journal of Physiology-Endocrinology and Metabolism

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“…To date, research on lncRNAs has focused on the role of lncRNAs in genetics, particularly in the regulation of transcription, post-transcription or epigenetics via the biological processes of histone modification, chromatin remodelling or DNA methylation [27]. Studies have also shown that lncRNAs are involved in various diseases, including DN [28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

The Long Noncoding RNA 150Rik Promotes Mesangial Cell Proliferation via miR-451/IGF1R/p38 MAPK Signaling in Diabetic Nephropathy

Zhang¹,

Sun²,

Peng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. However, the initiating molecular events triggering DN are unknown. Recently, long noncoding RNAs (lncRNAs) have been shown to play important roles in DN. Methods: The expression level of lncRNA 1500026H17Rik (150Rik for short) was measured by qRT-PCR (quantitative real-time PCR). Cell proliferation ability was detected by 5-Ethynyl-2’-deoxyuridine (EdU). The relationship between 150Rik and microRNA 451 (miR-451) was examined by luciferase assay and RNA immunoprecipitation (RIP) assay. Finally, the effect of 150Rik on cell proliferation through the miR-451/insulin-like growth factor 1 receptor (IGF1R)/mitogen-activated protein kinases (p38MAPK) pathway was detected by EdU, flow cytometry analysis, western blot. Results: We found that 150Rik, an evolutionarily conserved lncRNA, was significantly upregulated in renal tissue of db/db DN mice and in mesangial cells (MCs) cultured under a high glucose condition. Further, overexpression or knockdown of 150Rik was found to regulate cell proliferation in MCs. Moreover, 150Rik was found to interact with miR-451 in both a direct and argonaute-2 (Ago2)-dependent manner. Results also revealed that overexpression of 150Rik inhibited cell proliferation through the miR-451/IGF1R/p38MAPK pathway in MCs under the high glucose condition, while knockdown of 150Rik increased cell proliferation via the miR-451/IGF1R/p38MAPK pathway. Conclusion: Taken together, these results provide new insight into the association between 150Rik and the miR-451/IGF1R/p38MAPK signaling pathway during DN progression.

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“…Epigenetic modifications can cause changes in gene expression, without changing the DNA sequence ( Gibney and Nolan, 2010 ) and are self-perpetuating, dynamic, and reversible in response to the environment ( Beckerman et al., 2014 ). Many factors can influence epigenetic profiles, including hyperglycemia, hypoxia, and inflammation ( Lu et al., 2017 ). Epigenetic modifications can either be beneficial, or hamper GEnC function by changing the transcriptome, resulting in GEnC dysfunction and potentially disturbed cross-talk and pathogenesis of FSGS and DN.…”

Section: Epigenetic Modifications: a Potential Mechanism Involved In mentioning

confidence: 99%

“…DNA methylation can also inhibit gene expression via methyl binding proteins, which in turn recruit transcriptional co-repressors. DNA methylation at genes can modulate transcriptional elongation and alternative splicing ( Gibney and Nolan, 2010 ; Lu et al., 2017 ).…”

Section: Epigenetic Modifications: a Potential Mechanism Involved In mentioning

confidence: 99%

Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases

et al. 2020

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Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk via intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.

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Epigenetic Regulations in Diabetic Nephropathy

Cited by 63 publications

References 64 publications

ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications

ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications

The Long Noncoding RNA 150Rik Promotes Mesangial Cell Proliferation via miR-451/IGF1R/p38 MAPK Signaling in Diabetic Nephropathy

Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases

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