PMID- 37331680 OWN - NLM STAT- MEDLINE DCOM- 20230703 LR - 20230703 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 953 DP - 2023 Aug 15 TI - Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice. PG - 175866 LID - S0014-2999(23)00377-1 [pii] LID - 10.1016/j.ejphar.2023.175866 [doi] AB - 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 epigenomic 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-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFbeta1) 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 region 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. CI - Copyright (c) 2023. Published by Elsevier B.V. FAU - Sarwar, Md Shahid AU - Sarwar MS AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Cheng, David AU - Cheng D AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Peter, Rebecca Mary AU - Peter RM AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Shannar, Ahmad AU - Shannar A AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Chou, Pochung AU - Chou P AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Wang, Lujing AU - Wang L AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Wu, Renyi AU - Wu R AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Sargsyan, Davit AU - Sargsyan D AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Goedken, Michael AU - Goedken M AD - Office of Translational Science, Research Pathology Services, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Wang, Yujue AU - Wang Y AD - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. FAU - Su, Xiaoyang AU - Su X AD - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. FAU - Hart, Ronald P AU - Hart RP AD - Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Kong, Ah-Ng AU - Kong AN AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. Electronic address: kongt@pharmacy.rutgers.edu. LA - eng PT - Journal Article DEP - 20230616 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Receptors, Leptin) RN - 0 (leptin receptor, mouse) SB - IM MH - Animals MH - Mice MH - *Diabetes Mellitus/metabolism MH - *Diabetic Nephropathies/genetics/metabolism MH - Epigenesis, Genetic MH - Epigenomics MH - Kidney/metabolism MH - Mice, Inbred Strains MH - Receptors, Leptin/genetics/metabolism OTO - NOTNLM OT - DNA methylation OT - Diabetic nephropathy OT - Epigenetics OT - Gene expression OT - Metabolomic OT - TCA cycle COIS- Declaration of competing interest The authors declare no conflict of interest. EDAT- 2023/06/19 00:42 MHDA- 2023/06/30 06:42 CRDT- 2023/06/18 19:18 PHST- 2022/07/28 00:00 [received] PHST- 2023/06/14 00:00 [revised] PHST- 2023/06/15 00:00 [accepted] PHST- 2023/06/30 06:42 [medline] PHST- 2023/06/19 00:42 [pubmed] PHST- 2023/06/18 19:18 [entrez] AID - S0014-2999(23)00377-1 [pii] AID - 10.1016/j.ejphar.2023.175866 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Aug 15;953:175866. doi: 10.1016/j.ejphar.2023.175866. Epub 2023 Jun 16.