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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2019; 65(2): 22-30


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

  1. O.O.Bogomoletz Institute of Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine
  2. Private Higher Education Establishment Kyiv Medical University, Ukraine
DOI: https://doi.org/10.15407/fz65.02.022

Abstract

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.

Keywords: diabetes mellitus type 2; complications; endothelin-1; rs6842241 EDNRA gene and rs5351 EDNRB gene.

References

  1. Pankiv VI. Diabetes mellitus: diagnostic criteria, etiology and pathogenesis. Int Endocrinol J. 2013;8(56):53-64. [Ukrainian].
  2.  
  3. Type 2 Diabetes Complications. [Internet]. Available from: https://www. endocrineweb.com/conditions/type- 2-diabetes/type-2-diabetes-complications.
  4.  
  5. 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. CrossRef PubMed
  6.  
  7. Sinyachenko OV, Ziablitsev SV, Chernobryvtsev PA. Endothelial dysfunction in glomerulonephritis. Donetsk: New World; 2006. [Russian].
  8.  
  9. 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. CrossRef PubMed PubMedCentral
  10.  
  11. 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.
  12.  
  13. 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. CrossRef PubMed PubMedCentral
  14.  
  15. 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. CrossRef PubMed
  16.  
  17. IDF Diabetes Atlas Eighth Edition [Internet]; 2017:149. Available from: http://www.diabetesatlas.org/.
  18.  
  19. 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].
  20.  
  21. 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. CrossRef PubMed PubMedCentral
  22.  
  23. 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. CrossRef PubMed PubMedCentral
  24.  
  25. 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. CrossRef  
  26. 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. CrossRef PubMed
  27.  
  28. 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 CrossRef  
  29. 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. CrossRef  

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