Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice

被引：7

作者：

Sarwar, Md. Shahid ^{[1
]}

Cheng, David ^{[1
,2
]}

Peter, Rebecca Mary ^{[1
,2
]}

Shannar, Ahmad ^{[1
,2
]}

Chou, Pochung ^{[1
,2
]}

Wang, Lujing ^{[1
,2
]}

Wu, Renyi ^{[1
]}

Sargsyan, Davit ^{[1
,2
]}

Goedken, Michael ^{[3
]}

Wang, Yujue ^{[4
]}

Su, Xiaoyang ^{[4
]}

Hart, Ronald P. ^{[5
]}

Kong, Ah-Ng ^{[1
]}

机构：

[1] State Univ New Jersey, Rutgers, Ernest Mario Sch Pharm, Dept Pharmaceut, Piscataway, NJ 08854 USA

[2] Rutgers, State Univ New Jersey, Ernest Mario Sch Pharm, Grad Program Pharmaceut Sci, Piscataway, NJ 08854 USA

[3] Rutgers, State Univ New Jersey, Res Pathol Serv, Off Translat Sci, Piscataway, NJ 08854 USA

[4] Rutgers Canc Inst New Jersey, Metabol Shared Resource, New Brunswick, NJ 08901 USA

[5] Rutgers, State Univ New Jersey, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2023年 / 953卷

关键词：

Diabetic nephropathy; Metabolomic; TCA cycle; Epigenetics; DNA methylation; Gene expression; OXIDATIVE STRESS; DNA METHYLATION; KIDNEY-DISEASE; MOUSE; PATHWAYS; ASSOCIATION; MODEL; GENE;

D O I：

10.1016/j.ejphar.2023.175866

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches.Methods: The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epi-genomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing.Results: LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adeno-sylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGF & beta;1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter re-gion of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN.Conclusion: Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.

引用

页数：10

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