PATHOGENETIC ROLE OF ENDOTELIN-1 AND POLYMORPHISM OF ITS RECEPTORS IN DIABETES MELLITUS TYPE 2
S.V. Ziablytsev1, O.P. Chernobrytsev1, D.S. Ziablytsev2, O.O. Starodubska1, Ts.B. Abdriakhimova1
- O.O.Bogomoletz Institute of Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine
- Private Higher Education Establishment Kyiv Medical University, Ukraine
The aim of the study was to determine the pathogenetic role
of endothelin-1 (ET1) and the connection of the rs6842241
polymorphisms of the EDNRA gene and rs5351 of the EDNRB
gene with diabetes mellitus type 2 (DM2T) and its
complications in the cohort of Ukrainian patients. Surveyed
152 patients aged 53.9±8.4 years and 95 people in the control
group. Genetic polymorphisms were determined by real-time
polymerase chain reaction (TaqMan Mutation Detection
Assays Life-Technology; USA). The presence of an association
of elevated blood levels of ET1 (3.7-4.7 times) and NO
(1.4-1.5 times) with disease progression has been shown. The
increase in ET1 level was associated with the development of
retinopathy, nephropathy, determined by microalbuminuria
and glomerular filtration rate, sensory polyneuropathy and
arterial hypertension, and NO – with arterial hypertension and
lower limb macroangiopathy. Endothelin receptor gene polymorphisms
were associated with the development of DM2T:
for rs6842241, an increased risk was associated with a minor
allele A (odds ratio 1.87; 95% confidence interval 1.20-2.92;
P=0.005), for rs5351 with ancestral allele C (odds ratio 1.54;
95% confidence interval 1.05-2.25; P=0.026). The presence of
these alleles was associated with a higher blood level of ET1.
Risk A allele rs6842241 contributed to higher body mass index,
systolic and diastolic pressure and triglyceride level in blood
compared to allele C. Carriers of rs5351 risk allele C were ill
for three years longer, they had higher blood levels of urea and
creatinine, microalbuminuria, as well as a lower glomerular
filtration rate than T allele carriers. Thus, directly influencing
the clinical and laboratory parameters and the development of
complications, the rs6842241 and rs5351 endothelin receptor
genes reduced the severity of DM2T.
diabetes mellitus type 2; complications; endothelin-1; rs6842241 EDNRA gene and rs5351 EDNRB gene.
- Pankiv VI. Diabetes mellitus: diagnostic criteria, etiology and pathogenesis. Int Endocrinol J. 2013;8(56):53-64. [Ukrainian].
- Type 2 Diabetes Complications. [Internet]. Available from: https://www. endocrineweb.com/conditions/type- 2-diabetes/type-2-diabetes-complications.
- Pi X, Xie L, Patterson C. Emerging roles of vascular endothelium in metabolic homeostasis. Circ Res. 2018 Aug;123(4):477-94. doi: 10.1161/CIRCRESAHA.118.313237.
- Sinyachenko OV, Ziablitsev SV, Chernobryvtsev PA. Endothelial dysfunction in glomerulonephritis. Donetsk: New World; 2006. [Russian].
- Zanatta CM, Crispim D, Sortica DA, Klassmann LP, Gross JL, Gerchman F, Canani LH. Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2015 Nov 19;7:103. doi: 10.1186/s13098-015-0093-5.
- Li W, Abdul Y, Ward R, Ergul A. Endothelin and diabetic complications: a brain-centric view. Physiol Res. 2018 Jun 27;67(Supplementum 1):S83-S94.
- Bregar D, Cilenšek I, Mankoč S, Reschner A, Petrovič D, Globočnik Petrovič M. The joint effect of the endothelin receptor B gene (EDNRB) polymorphism rs10507875 and nitric oxide synthase 3 gene (NOS3) polymorphism rs869109213 in Slovenian patients with type 2 diabetes mellitus and diabetic retinopathy. Bosn J Basic Med Sci. 2018 Feb 20;18(1):80-6. doi: 10.17305/bjbms.2017.2244.
- Georgianos PI, Agarwal R. Endothelin A receptor antagonists in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017 Sep;26(5):338-44. doi: 10.1097/ MNH.0000000000000342.
- IDF Diabetes Atlas Eighth Edition [Internet]; 2017:149. Available from: http://www.diabetesatlas.org/.
- On approval and implementation of medical-technological documents for the standardization of medical aid in type 2 diabetes. Unified clinical protocol for primary and secondary (specialized) medical aid "Diabetes type 2". Order of the Ministry of Health of Ukraine: Kyiv;2012 Dec 21;1118. [Ukrainian].
- Martínez-Barquero V, de Marco G, Martínez-Hervas S, Rentero P, Galan-Chilet I, Blesa S, Morchon D. et al. Polymorphisms in endothelin system genes, arsenic levels and obesity risk. PLoS One. 2015 Mar 23;10(3):e0118471. doi: 10.1371/journal.pone.0118471.
- Dubovyk YI, Oleshko TB, Harbuzova VY, Ataman AV. Positive association between EDN1 rs5370 (Lys198Asn) polymorphism and large artery stroke in a Ukrainian population. Dis Markers. 2018 Apr 3;2018:1695782. doi:10.1155/2018/1695782.
- Park K, Mima A, Li Q, Rask-Madsen C, He P, Mizutani K, Katagiri S. et al. Insulin decreases atherosclerosis by inducing endothelin receptor B expression. JCI Insight. 2016 May 5;1(6). pii: e86574.
- Rautureau Y, Coelho SC, Fraulob-Aquino JC, Huo KG, Rehman A, Offermanns S, Paradis P, Schiffrin EL. Inducible human endothelin-1 overexpression in endothelium raises blood pressure via endothelin type A receptors. Hypertension. 2015 Aug;66(2):347-55. doi: 10.1161/ HYPERTENSIONAHA.115.05168.
- Mogilevskyy SIu, Bushuieva OV, Ziablitsev SV, Natrus LV. Relationship of the AKR1B1 rs759853 and rs9640883 with the development of diabetic retinopathy. J.Ophthal. 2017;2:3-7. [Ukrainian] CrossRef
- Hudz AS, Zakharevych GIe, Pentrenko OV, Ziablitsev SV, Dzhordzhua VS. Relationships of vascular endothelial growth factor (VEGFA) with stage of diabetic retinopathy and disease duration in patients with type 2 diabetes mellitus. J.Ophthalmol. 2017;6:11-6.[Ukrainian] https://doi. org/10.31288/oftalmolzh/2018/2/1116.