Histone Acetylation Regulates Natriuretic Peptides and Neprilysin Gene Expressions in Diabetic Cardiomyopathy and Nephropathy

Author(s): Vajir Malek, Nisha Sharma, Anil Bhanudas Gaikwad*.

Journal Name: Current Molecular Pharmacology

Volume 12 , Issue 1 , 2019

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Graphical Abstract:


Background: Natriuretic peptide system (NPS) alterations are involved in pathogenesis of diabetic cardiomyopathy (DCM) and nephropathy (DN), however its epigenetic regulation is still unclear. Interestingly, histone acetylation epigenetically regulates neprilysin expression in Alzheimer’s disease.

Objectives: The present study was aimed at delineating role of histone acetylation in regulation of NPS in DCM and DN.

Methods: Streptozotocin (55 mg/kg, i.p.)-induced diabetic male Wistar rats were used to mimic pathogenesis of DCM and DN. After haemodynamic measurements, all the rat’s plasma, heart and kidney were collected for biochemistry, ELISA, protein isolation and western blotting, RT-PCR and chromatin immunoprecipitation (ChIP) assay.

Results: Diabetic rats heart and kidney exhibited activation of NF-κB and TGF-β signalling with increased histone acetyl transferases (PCAF/CBP) expressions and augmented H2AK5Ac, H2BK5Ac, H3K18Ac, and H4K8Ac levels. ChIP assay results showed increased enrichment of H3K18Ac and H2BK5Ac at Nppa, Nppb (Heart) and Mme promoter (Heart/Kidney) in diabetic rats. Enrichment of H2AK5Ac was augmented on Nppa and Mme promoters in diabetic heart, while it remained unchanged on Nppb promoter in heart and Mme promoter in kidney.

Conclusion: Augmented histone acetylation at promoter regions of NPS gene(s), at least in a part, is responsible for increased expressions of ANP, BNP and NEP in diabetic heart and kidney. Hence, histone acetylation inhibitors can be considered as novel therapeutic targets against DCM and DN.

Keywords: Natriuretic peptides, neprilysin, histone acetylation, PCAF/CBP, diabetic cardiomyopathy, diabetic nephropathy.

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Article Details

Year: 2019
Page: [61 - 71]
Pages: 11
DOI: 10.2174/1874467212666181122092300
Price: $58

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