Histamine causes an imbalance between pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of diabetic retina via H4 receptor/p38 MAPK axis.
animal experimentation
cells
diabetic retinopathy
eye diseases
Journal
BMJ open diabetes research & care
ISSN: 2052-4897
Titre abrégé: BMJ Open Diabetes Res Care
Pays: England
ID NLM: 101641391
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
20
06
2020
revised:
21
10
2020
accepted:
29
10
2020
entrez:
17
12
2020
pubmed:
18
12
2020
medline:
22
6
2021
Statut:
ppublish
Résumé
Systemic histaminergic activity is elevated in patients with diabetes mellitus. There are a few studies suggesting that histamine is implicated in the pathogenesis of diabetes, but the exact role of histamine in the development of diabetic retinopathy is unclear. The aim of this study was to investigate the role of histamine receptor H4 (HRH4) in the regulation of retinal pigment epithelium (RPE)-derived pro-angiogenic and anti-angiogenic factors under diabetic conditions. The levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), histamine and histidine decarboxylase (HDC) in the serum and vitreous samples of patients with diabetes were compared with those of patients without diabetes. The effect of hyperglycemia on expression levels of HRH4, VEGF, IL-6 and pigment epithelium-derived factor (PEDF) in the RPE was determined. The role of HRH4 in high glucose-induced regulation of VEGF, IL-6 and PEDF in ARPE-19 cells and the underlying regulatory mechanism were verified using an RNA interference-mediated knockdown study. The serum and vitreous levels of VEGF, IL-6, histamine and HDC were more increased in patients with diabetic retinopathy than in patients without diabetes. HRH4 was overexpressed in RPE both in vitro and in vivo. Histamine treatment upregulated VEGF and IL-6 and downregulated PEDF expression in ARPE-19 cells cultivated under hyperglycemic conditions. Hyperglycemia-induced phosphorylation of p38 and subsequent upregulation of VEGF and IL-6 and downregulation of PEDF were dampened by small interfering RNA-mediated knockdown of HRH4 in ARPE-19 cells. Taken together, HRH4 was a critical regulator of VEGF, IL-6 and PEDF in the RPE under hyperglycemic conditions and the p38 mitogen-activated protein kinase pathway mediated this regulatory mechanism.
Identifiants
pubmed: 33328159
pii: 8/2/e001710
doi: 10.1136/bmjdrc-2020-001710
pmc: PMC7745681
pii:
doi:
Substances chimiques
Angiogenesis Inducing Agents
0
Vascular Endothelial Growth Factor A
0
Histamine
820484N8I3
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Invest Ophthalmol Vis Sci. 1988 Aug;29(8):1201-4
pubmed: 2971025
Ophthalmology. 2010 Jun;117(6):1078-1086.e2
pubmed: 20416952
Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2158-64
pubmed: 20071676
JAMA. 2015 Nov 24;314(20):2137-2146
pubmed: 26565927
Retina. 1995;15(2):134-40
pubmed: 7624601
Immunol Invest. 2004 May;33(2):213-33
pubmed: 15195698
Ophthalmology. 2013 Oct;120(10):2013-22
pubmed: 23706949
Metabolism. 1990 Aug;39(8):815-8
pubmed: 2377078
Arch Ophthalmol. 2004 Apr;122(4):552-63
pubmed: 15078674
Diabetologia. 2004 Jul;47(7):1210-1222
pubmed: 15232685
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18751-6
pubmed: 19841260
Diabetes Res. 1988 Jan;7(1):31-4
pubmed: 3402164
Mol Vis. 2016 Jul 14;22:761-70
pubmed: 27440994
Eur Rev Med Pharmacol Sci. 2018 Sep;22(18):5789-5796
pubmed: 30280757
Br J Pharmacol. 2013 Sep;170(1):58-66
pubmed: 23488566
Mol Vis. 2013 Nov 01;19:2165-72
pubmed: 24194637
Metabolism. 1989 Mar;38(3):243-7
pubmed: 2918844
Invest Ophthalmol Vis Sci. 2002 Mar;43(3):821-9
pubmed: 11867604
Blood. 2013 Mar 14;121(11):2154-64
pubmed: 23315169
Inflamm Res. 2009 Apr;58 Suppl 1:45-6
pubmed: 19271148
Biochem Pharmacol. 2015 Dec 1;98(3):432-9
pubmed: 26385311
J Clin Immunol. 2012 Jun;32(3):574-86
pubmed: 22362129
Inflamm Res. 2007 Apr;56 Suppl 1:S37-8
pubmed: 17806171
Front Pharmacol. 2018 Mar 20;9:240
pubmed: 29615910
Diabetologia. 1997 Jun;40(6):726-30
pubmed: 9222654
Cytokine. 2017 Jul;95:126-135
pubmed: 28282610
J Leukoc Biol. 2014 Sep;96(3):411-8
pubmed: 24799603
Invest Ophthalmol Vis Sci. 2002 May;43(5):1574-80
pubmed: 11980876
Clin Exp Immunol. 1998 Apr;112(1):34-43
pubmed: 9566787
J Cell Biochem. 2013 May;114(5):1009-19
pubmed: 23225320
Lab Invest. 2007 Jun;87(6):548-58
pubmed: 17401436
Invest Ophthalmol Vis Sci. 2015 May;56(5):2971-9
pubmed: 25829413