Histone Acetylation Regulates Natriuretic Peptides and Neprilysin Gene Expressions in Diabetic Cardiomyopathy and Nephropathy.
Acetylation
Animals
Diabetes Mellitus, Experimental
/ chemically induced
Diabetic Cardiomyopathies
/ metabolism
Diabetic Nephropathies
/ metabolism
Gene Expression
Hemodynamics
Histone Acetyltransferases
/ genetics
Histones
/ metabolism
Kidney
/ metabolism
Male
Myocardium
/ metabolism
NF-kappa B
/ metabolism
Natriuretic Peptides
/ genetics
Neprilysin
/ genetics
Promoter Regions, Genetic
Rats
Rats, Wistar
Receptors, Atrial Natriuretic Factor
/ genetics
Signal Transduction
Natriuretic peptides
PCAF/CBP
diabetic cardiomyopathy
diabetic nephropathy
histone acetylation
neprilysin.
Journal
Current molecular pharmacology
ISSN: 1874-4702
Titre abrégé: Curr Mol Pharmacol
Pays: United Arab Emirates
ID NLM: 101467997
Informations de publication
Date de publication:
2019
2019
Historique:
received:
21
08
2018
revised:
05
11
2018
accepted:
07
11
2018
pubmed:
23
11
2018
medline:
18
6
2019
entrez:
23
11
2018
Statut:
ppublish
Résumé
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. The present study was aimed at delineating role of histone acetylation in regulation of NPS in DCM and DN. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30465518
pii: CMP-EPUB-94706
doi: 10.2174/1874467212666181122092300
doi:
Substances chimiques
Histones
0
NF-kappa B
0
Natriuretic Peptides
0
Histone Acetyltransferases
EC 2.3.1.48
Neprilysin
EC 3.4.24.11
Receptors, Atrial Natriuretic Factor
EC 4.6.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
61-71Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.