Value of the NOS3 gene Т786С polymorphism for early diagnosis of kidney damage in patients with essential arterial hypertension

Background. Essential arterial hypertension (AH) is a global problem of the healthcare system. Kidney damage could aggravate the course of the disease, and genetic factors play an important role in the development of hypertensive nephropathy: approximately 50% of patients are carriers of genetic polymorphisms that predispose to the occurrence of hypertensive nephropathy. Objective. Studying the relationship between genetical disorders and features of intrarenal blood flow among patients with AH. Design and methods. 114 patients (49 men and 65 women) aged 35 to 58 years with stage I–II hypertension and 1–3 degrees of arterial hypertension were examined. Duplex scanning of renal arteries was performed using a Vivid-7 Dimension ultrasound scanner, genotyping of the Т786С polymorphism of the NOS3 gene using a real-time polymerase chain reaction; the calculated glomerular filtration rate (using the CKD-EPI formula) was analyzed. The examined patients were divided into 2 groups: the 1st group included individuals with glomerular filtration rate (GFR) greater than or equal to 60 ml/min/1,73 m² (32 men and 40 women), the 2nd group — with GFR 45–59 ml/min/1,73 m² (17 men and 25 women). Results. In patients with hypertension with GFR 45–59 ml/min/1,73 m2 , the predominance of the CC genotype and allele-C was found, and among patients with GFR greater than or equal to 60 ml/min/1,73 m², the TC genotype and allele-Т prevailed. In the second group, higher values of peripheral resistance indices were observed in comparison with the first group. It was also found that individuals with TC and CC genotypes had higher indices of peripheral resistance of intrarenal blood flow compared to patients with TT genotype. Conclusion. The presence in the genotype of patients with arterial hypertension of the 786C allele and the CC genotype of the NOS3 gene can predispose to early kidney damage, and an increase in the indices of peripheral resistance of blood flow in the interlobar renal arteries can serve as a criterion for the development of hypertensive nephropathy in patients with arterial hypertension.

arterial hypertension, glomerular filtration rate, renal blood flow, polymorphism of the NOS3 gene

1. Badin YuV, Fomin IV, Belenkov YuN, et al. EPOCHAAH 1998–2017. Dynamics of prevalence, awareness of arterial hypertension, treatment coverage, and effective control of blood pressure in the european part of the Russian Federation. Kardiologiya=Cardiology. 2019; 59 (1S): 34–42. In Russian

2. Shalnova SA, Konradi AO, Balanova YuA, et al. What factors do influence arterial hypertension control in Russia. Kardiovaskulyarnaya terapiya i profilaktika=Cardiovascular therapy and prevention. 2018; 17 (4): 53–60. In Russian [Шальнова С.А., Конради А.О., Баланова Ю.А. и др. Какие факторы влияют на контроль артериальной гипертонии в России. Кардиоваскулярная терапия и профилактика. 2018; 17 (4): 53–60].

3. Mann JF, Gerstein HC, Dulau-Florea I, et al. Cardiovascular risk in patients with mild renal insufficiency. Kidney Int Suppl. 2003; 84: S192–196.

4. Schiffrin EL, Lipman ML, Mann JFE. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007; 116 (1): 85–97.

5. Dolgikh VV, Kolesnikova LI. Pathogenesis of essential arterial hypertension in children. Irkutsk: VSNTs SO RAMS, 1999. p. 218. In Russian

6. Shakhanov AV, Uryasev OM. Effect of the NOS3 786C/T polymorphism on the levels of nitric oxide in patients with asthma and comorbid hypertension. Vestnik Rossijskogo gosudarstvennogo medicinskogo universiteta=Bulletin of the Russian State Medical University. 2018; 3: 56–60. In Russian.

7. Sedashkina OA, Makovetskaya GA, Pechkurov DV. Role of some genetic factors in chronic kidney disease progressing in children. Prakticheskaya medicina=Practical medicine. 2015; 7 (92): 72–77. In Russian

8. Zhang X, Lynch AI, Davis BR, et al. Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study. PLoS One. 2012; 7 (3): e34217.

9. Grunfeld S, Hamilton CA, Mesaros S, et al. Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats. Hypertension. 1995; 26 (6 Pt 1): 854–857.

10. Sever PS, Poulter NR. Management of hypertension: is it the pressure or the drug? Blood pressure reduction is not the only determinant of outcome. Circulation. 2006; 113: 2754–2774.

11. Casas JP, Cavalleri GL, Bautista LE, et al. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review. Am J Epidemiol. 2006; 164 (10): 921–935.

12. Degaeva TA, Radajkina OG, Usanova AA, et al. Polymorphism of the nitric oxide-3 endothelial synthase gene in patients with arterial hypertension and type II diabetes living in the territory of the Republic of Mordovia. Vestnik Mordovskogo universiteta=Bulletin of the Mordovian University. 2013; 1–2: 53–56. In Russian

13. Guzik TJ, Black E, West NE, et al. Relationship between the G894T polymorphism (Glu298Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis. Am J Med Genet. 2001; 100 (2): 130–137.

14. Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep. 2003; 5 (1):19–25.

15. Chernova AA, Nikulina SYu, Maksimov VN, et al. Polymorphic allele variants of eNOS gene in patients with disorders of cardiac conduction. Kardiologiya=Cardiology. 2014; 54 (10): 26–31. In Russian

16. Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Clinical and pharmacogenetic impact of endothelial nitric oxide synthase polymorphisms on cardiovascular diseases. Nitric Oxide. 2017; 63: 39–51.

17. Bruno RM, Salvati A, Barzacchi M, et al. Predictive value of dynamic renal resistive index (DRIN) for renal outcome in type 2 diabetes and essential hypertension: a prospective study. Cardiovasc Diabetol. 2015; 14: 63.

18. Zhuravleva OA, Vinniczkaya IV, Koshelskaya OA. Intrarenal vascular resistance in patients with arterial hypertension and diabetes mellitus: relation to the level of arterial blood pressure and value of glomerular filtration rate. Sibirskij medicinskij zhurnal=Siberian medical journal. 2016; 31 (1): 17–21. In Russian

19. Doi Y, Iwashima Y, Yoshihara F, et al. Renal resistive index and cardiovascular and renal outcomes in essential hypertension. Hypertension. 2012; 60 (3): 770–777.

20. Koshelskaya OA, Zhuravleva OA, Karpov RS. Markers of chronic kidney disease in high-risk hypertensive patients: relationship with abnormal circadian blood pressure profile and intrarenal vascular resistance. Arterial`naya gipertenziya=Arterial hypertension. 2018; 24 (4): 478–489. In Russian

21. Bige N, Levy PP, Callard P, et al. Renal arterial resistive index is associated with severe histological changes and poor renal outcome during chronic kidney disease. BMC Nephrol. 2012; 13: 139.

22. Sugiura T, Wada A. Resistive index predicts renal prognosis in chronic kidney disease. Nephrol Dial Transplant. 2009; 24 (9): 2780–2785.

23. Bebyakova NA, Khromova AV, Feliksova OM, et al. T-786C polymorphism in endothelial nitric oxide synthase gene is assotiated with peripheral vasoconstriction. Fundamental`nye issledovaniya=Fundamental research. 2013; 12 (2): 176–179. In Russian