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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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.

[1]
Li, G.; Zhang, P.; Wang, J.; An, Y.; Gong, Q.; Gregg, E.W.; Yang, W.; Zhang, B.; Shuai, Y.; Hong, J. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study:A 23-year follow-up study. Lancet Diabetes Endocrinol., 2014, 2, 474-480.
[2]
Chong, C-R.; Clarke, K.; Levelt, E. Metabolic remodelling in diabetic cardiomyopathy. Cardiovasc. Res., 2017, 113, 422-430.
[3]
Frati, G.; Schirone, L.; Chimenti, I.; Yee, D.; Biondi-Zoccai, G.; Volpe, M.; Sciarretta, S. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc. Res., 2017, 113, 378-388.
[4]
Papadopoulou Marketou, N.; Chrousos, G.P.; Kanaka Gantenbein, C. Diabetic nephropathy in type 1 diabetes: A review of early natural history, pathogenesis, and diagnosis. Diabetes Metab. Res. Rev., 2017.
[5]
Malek, V.; Gaikwad, A.B. Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications? Biomed. Pharmacother., 2017, 90, 752-759.
[6]
Moro, C. Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity. Expert Opin. Ther. Targets, 2016, 20, 1445-1452.
[7]
Levin, E.R.; Gardner, D.G.; Samson, W.K. Natriuretic peptides. N. Engl. J. Med., 1998, 339, 321-328.
[8]
Felker, G.M.; Anstrom, K.J.; Adams, K.F.; Ezekowitz, J.A.; Fiuzat, M.; Houston-Miller, N.; Januzzi, J.L.; Mark, D.B.; Piña, I.L.; Passmore, G. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: A randomized clinical trial. JAMA, 2017, 318, 713-720.
[9]
Keating, S.; El Osta, A. Epigenetic changes in diabetes. Clin. Genet., 2013, 84, 1-10.
[10]
Perrino, C.; Barabási, A-L.; Condorelli, G.; Davidson, S.M.; De Windt, L.; Dimmeler, S.; Engel, F.B.; Hausenloy, D.J.; Hill, J.A.; Van Laake, L.W. Epigenomic and transcriptomic approaches in the post-genomic era: Path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc. Res., 2017, 113, 725-736.
[11]
Keating, S.T.; van Diepen, J.A.; Riksen, N.P.; El-Osta, A. Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia, 2018, 61, 6-20.
[12]
Reddy, M.A.; Natarajan, R. Recent developments in epigenetics of acute and chronic kidney diseases. Kidney Int., 2015, 88, 250-261.
[13]
Reddy, M.A.; Sumanth, P.; Lanting, L.; Yuan, H.; Wang, M.; Mar, D.; Alpers, C.E.; Bomsztyk, K.; Natarajan, R. Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int., 2014, 85, 362-373.
[14]
Kadakol, A.; Malek, V.; Goru, S.K.; Pandey, A.; Sharma, N.; Gaikwad, A.B. Esculetin ameliorates insulin resistance and type 2 diabetic nephropathy through reversal of histone H3 acetylation and H2A lysine 119 monoubiquitination. J. Funct. Foods, 2017, 35, 256-266.
[15]
Pharaon, L.F.; El-Orabi, N.F.; Kunhi, M.; Al Yacoub, N.; Awad, S.M.; Poizat, C. Rosiglitazone Promotes Cardiac Hypertrophy and Alters Chromatin Remodeling in Isolated Cardiomyocytes. Toxicol. Lett., 2017, 280, 151-158.
[16]
Keating, S.T.; Plutzky, J.; El-Osta, A. Epigenetic Changes in Diabetes and Cardiovascular Risk. Circ. Res., 2016, 118, 1706-1722.
[17]
Berthiaume, J.M.; Hsiung, C-h.; Austin, A.B.; McBrayer, S.P.; Depuydt, M.M.; Chandler, M.P.; Miyagi, M.; Rosca, M.G. Methylene blue decreases mitochondrial lysine acetylation in the diabetic heart. Mol. Cell. Biochem., 2017, 432, 7-24.
[18]
Huang, J.; Wan, D.; Li, J.; Chen, H.; Huang, K.; Zheng, L. Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renal injury. Epigenetics, 2015, 10, 62-71.
[19]
Wang, H.; Sun, M.; Yang, H.; Tian, X.; Tong, Y.; Zhou, T.; Zhang, T.; Fu, Y.; Guo, X.; Fan, D. Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells. J. Neurochem., 2014, 131, 4-11.
[20]
Chen, H.; Li, J.; Jiao, L.; Petersen, R.B.; Li, J.; Peng, A.; Zheng, L.; Huang, K. Apelin inhibits the development of diabetic nephropathy by regulating histone acetylation in Akita mouse. J. Physiol., 2014, 592, 505-521.
[21]
Wang, Y.; Wang, Y.; Luo, M.; Wu, H.; Kong, L.; Xin, Y.; Cui, W.; Zhao, Y.; Wang, J.; Liang, G. Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. BBA-Mol. Basis. Dis., 2015, 1852, 34-46.
[22]
Kerridge, C.; Belyaev, N.D.; Nalivaeva, N.N.; Turner, A.J. The Aβ-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain. J. Neurochem., 2014, 130, 419-431.
[23]
Kilkenny, C.; Browne, W.J.; Cuthill, I.C.; Emerson, M.; Altman, D.G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol., 2010, 8, e1000412.
[24]
Malek, V.; Bhanudas Gaikwad, A. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy. Cardiovasc. Res., 2018.
[http://dx.doi.org/10.1093/cvr/cvy226]
[25]
Goru, S.K.; Kadakol, A.; Pandey, A.; Malek, V.; Sharma, N.; Gaikwad, A.B. Histone H2AK119 and H2BK120 mono-ubiquitination modulate SET7/9 and SUV39H1 in type 1 diabetes-induced renal fibrosis. Biochem. J., 2016, 473, 3937-3949.
[26]
Goru, S.K.; Kadakol, A.; Malek, V.; Pandey, A.; Sharma, N.; Gaikwad, A.B. Diminazene aceturate prevents nephropathy by increasing glomerular Ace2 and At2 receptor expression in a rat model of type1 diabetes. Br. J. Pharmacol., 2017, 174, 3118-3130.
[27]
Curtis, M.J.; Bond, R.A.; Spina, D.; Ahluwalia, A.; Alexander, S.; Giembycz, M.A.; Gilchrist, A.; Hoyer, D.; Insel, P.A.; Izzo, A.A. Experimental design and analysis and their reporting: new guidance for publication in BJP. Br. J. Pharmacol., 2015, 172, 3461-3471.
[28]
Cosson, S.; Kevorkian, J. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab., 2003, 29, 455-466.
[29]
Ryu, Y.; Jin, L.; Kee, H.J.; Piao, Z.H.; Cho, J.Y.; Kim, G.R.; Choi, S.Y.; Lin, M.Q.; Jeong, M.H. Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity. Sci. Rep., 2016.
[http://dx.doi.org/10.1038/srep34790]
[30]
Shah, M.S.; Brownlee, M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ. Res., 2016, 118, 1808-1829.
[31]
Dronavalli, S.; Duka, I.; Bakris, G.L. The pathogenesis of diabetic nephropathy. Nat. Rev. Endocrinol., 2008, 4, 444-452.
[32]
Tessarz, P.; Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol., 2014, 15, 703-708.
[33]
Deb, D.K.; Bao, R.; Li, Y.C. Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney. FASEB J., 2017, 31, 2065-2075.
[34]
Miao, F.; Chen, Z.; Genuth, S.; Paterson, A.; Zhang, L.; Wu, X.; Li, S.M.; Cleary, P.; Riggs, A.; Harlan, D.M. Evaluating the Role of Epigenetic histone modifications in the Metabolic Memory of Type 1 Diabetes. Diabetes, 2014, 63, 1748-1762.
[35]
Kadiyala, C.S.R.; Zheng, L.; Du, Y.; Yohannes, E.; Kao, H-Y.; Miyagi, M.; Kern, T.S. Acetylation of retinal histones in diabetes increases inflammatory proteins effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC). J. Biol. Chem., 2012, 287, 25869-25880.
[36]
Miao, F.; Gonzalo, I.G.; Lanting, L.; Natarajan, R. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J. Bio Chem., 2004, 279, 18091-18097.
[37]
Li, Y.; Li, X.; He, K.; Li, B.; Liu, K.; Qi, J.; Wang, H.; Wang, Y.; Luo, W. C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy. FASEB J., 2018, 32, 2269-2279.
[38]
Kato, M.; Dang, V.; Wang, M.; Park, J.T.; Deshpande, S.; Kadam, S.; Mardiros, A.; Zhan, Y.; Oettgen, P.; Putta, S. TGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy. Sci. Signal., 2013, 6, ra43.
[39]
Yuan, H.; Reddy, M.A.; Sun, G.; Lanting, L.; Wang, M.; Kato, M.; Natarajan, R. Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells. Am. J. Physiol. Renal Physiol., 2013, 304, F601-F613.
[40]
Chen, B.; Xiong, Z.; Ma, Y.; Liu, C.; Dong, Y. Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signalling pathway. Heart, 2011, 97(3)
[41]
Kim, A.; Yun, J-M. Combination treatments with luteolin and fisetin enhance anti-inflammatory effects in high glucose-treated THP-1 cells through histone acetyltransferase/histone deacetylase regulation. J. Med. Food, 2017, 20, 782-789.
[42]
Shi, M.; Lu, X-J.; Zhang, J.; Diao, H.; Li, G.; Xu, L.; Wang, T.; Wei, J.; Meng, W.; Ma, J-L. Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53-and caspase-3-mediated mechanisms. Oncotarget, 2016, 7, 22623-22631.
[43]
Kato, M.; Yuan, H.; Xu, Z-G.; Lanting, L.; Li, S-L.; Wang, M.; Hu, M.C-T.; Reddy, M.A.; Natarajan, R. Role of the Akt/FoxO3a pathway in TGF-β1-mediated mesangial cell dysfunction: A novel mechanism related to diabetic kidney disease. J. Am. Soc. Nephrol., 2006, 17, 3325-3335.
[44]
Wang, Z.; Yang, D.; Zhang, X.; Li, T.; Li, J.; Tang, Y.; Le, W. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One, 2011, 6.


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Article Details

VOLUME: 12
ISSUE: 1
Year: 2019
Page: [61 - 71]
Pages: 11
DOI: 10.2174/1874467212666181122092300
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