Renalase rs2296545 variant improve hypertension susceptibility by modifying binding affinity to catecholamines in obstructive sleep apnea

Abstract

Obstructive sleep apnea (OSA), a condition often linked with hypertension, has an undefined relationship with renalase, a protein known for regulating blood pressure. This study aimed to investigate the relationship between serum renalase levels as well as renalase functional single nucleotide polymorphism (SNP) rs2296545 variant and hypertension in a Han Chinese OSA population. 126 subjects underwent serum renalase detection, with linear regression being performed to evaluate the relationship between serum renalase levels and OSA-related traits. Additional 4275 subjects were obtained rs2296545 genotype information by SNP microarray. And binary logistic regression was used to assess the effect of rs2296545 on hypertension risk. Molecular dynamics simulation and molecular docking were utilized to access the protein structures and the interplay between protein and catecholamines of wild-type and rs2296545 mutant renalase. The results showed that serum renalase levels were significantly higher in the severe OSA group. Further analysis showed renalase levels were positively correlated with blood pressure in the non-OSA group and negatively correlated in the severe OSA group. For rs2296545 polymorphism analysis, the hypertension risk significantly increased for the recessive model CC/GG + CG (OR = 1.211, 95% CI: 1.025-1.431) and the additive model CC/CG (OR = 1.223, 95% CI: 1.025-1.458) in the severe OSA. The rs2296545 polymorphism affected protein structure, and led to increase binding free energy, weakening interactions between renalase and catecholamines. In conclusion, serum renalase levels had independent association with blood pressure. And rs2296545 polymorphism may influence on susceptibility to hypertension by altering protein ability to bind to catecholamines, which might contribute to the intervention of hypertension in the OSA population.

Keywords: Hypertension; Obstructive sleep apnea; Renalase; Single nucleotide polymorphism..

Fig. 1

Correlation of serum renalase levels with hypertension and OSA. A Serum renalase levels were significantly higher in the OSA population compared to the non-OSA population. B Serum renalase levels are elevated when patients have hypertension or OSA. In the non-OSA group, serum renalase levels were seen to be elevated in the hypertension subgroup compared to the non-hypertension group. In the severe OSA group, compared to the non-hypertension subgroup, the serum renalase levels in the hypertension subgroup decreased. ns: no significance; *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 2

A The RMSD of renalase(37Glu) stabilizes faster compared to renalase(37Asp). B The structural integrity of the renalase protein conformation undergoes perturbation, resulting in increased flexibility in renalase(Asp37). C The increased density in renalase (37Asp) may reduce the enzymatic activity pocket, impacting renalase substrate binding

Fig. 3

Renalase (37Glu) on the left and renalase (37Asp) on the right. A Adrenaline; (B): norepinephrine; (C): isoprenaline; (D): dopamine. I: Binding mode of wild-type or mutant renalase proteins to individual catecholamines; II: Three-dimensional interactions of renalase proteins and catecholamines; III: Two-dimensional interactions of renalase proteins and catecholamines