Biological Effect And Production Mechanism About Autoantibodies Against Angiotensin AT₁ Receptor In Patients With Essential Hypertension

Partâ… The mechanism of signal transduction in rat VSMCproliferation induced by autoantibodies against angiotensin AT₁receptor from essential hypertensivesBackground and objective:The autoantibodies against angiotension AT₁ receptor(AT₁-AA) have been discovered in the patients with malignant hypertensive,preeclampsiaand essential hypertension (EH).Some studies have demonstrated the autoantiboies areinvolved in the immunopathogenesis of hypertension and have an agonist-like activityeffect similar to angiotensinâ…¡(Angâ…¡).We further expound the mechanism of signaltransduction induced by autoantibodies against angiotensin AT₁ receptor fromhypertensives.Methods:The rat VSMCs were cultured and identified.The autoantiboies against AT₁receptor were purified from sera of the primary hypertension patients by ammonium sulfateprecipitation and affinity chromatography.Then the AT₁-AA collected was detected byELISA and activated cells with 1:40 and judged the effect on rat VSMC proliferation bythe method of BrdU incorporation in different treatment groups.The activation of signalingmolecules were detected by western blotting and electrophoretic mobility shift assay(EMSA) in cultured rat VSMCs. Results:The AT₁-AA caused a significant rat VSMC proliferation similar to the Angâ…¡during 0～24 h.The term levels of NF-κB,phosphorylated JAK2 (pJAK2),phosphorylated STAT1 (pSTAT1) and phosphorylated STAT3 (pSTAT3) molecules wereincreased in response to the autoantibodies.In contrast,the activation of NF-κB andJAK-STAT was blocked by Losartan,PDTC (Pyrrolidinedithiocarbamate,a specificinhibitor of NF-κB) and AG490 (a specific inhibitor of the JAK2 tyrosine kinase)respectively.The expressions of NF-κB,the pSTAT1 and pSTAT3 reached peak levels atdifferent time stages;Moreover,the gray relative value showed that activation of pSTAT3was more significant than that of STAT1 induced by AT₁-AA.Conclusion:These results suggest that the autoantiboies against AT₁-receptor have anagonist-like activity effect similar to Angâ…¡in VSMCs proliferation,and the NF-κB andJAK-STAT proteins play essential roles.Besides,it is different from AngI that STAT3 isthe main downstream activatory molecule in JAK-STAT signaling pathway.Partâ…¡HLA-DRB1,-DQB1 polymorphism and autoantibodiesagainst angiotension AT₁ receptors in Chinese patients with essentialhypertensionBackground and objective:The autoantibodies against angiotension AT₁ receptors(AT₁-AAs) have been discovered in patients with preeclampsia,malignant hypertensivesand essential hypertension (EH);however,the mechanism of autoantibody productionremains to be investigated.This study would analyze the association of AT₁-AAs and HLApolymorphism.Methods:We enrolled 394 patients with EH and 224 normotensives in this study.Autoantibodies in sera of donors were detected by ELISA.The subject's clinical data wascollected,including gender,age,body mass index,blood pressure,smoking and diabetes.The patients and the controls were classified respectively into the autoantibody positive group and autoantibody negative one.DNA typing for HLA-DRB1 and HLA-DQB1 alleleswas detected by PCR amplification with sequence-specific primers.Results:Thirteen HLA-DRB1 and seven DQB1 alleles were found in this population.We observed the differences of HLA-DRB1 and HLA-DQB1 allele frequency between EHand normotensives group.The haplotype HLA-DQB1^*06- DRB1^*13 was an independentrisk factor for EH (adjusted P=0.014,OR 3.138,95% CI 1.259-7.819) in the wholepopulation.HLA-DRB1^*04 and HLA-DRB1^*14 (respectively P=0.001,OR 3.056,95%CI1.562-5.974;P=0.033,OR 2.528,95%CI 1.080-5.914) were related to AT₁-AA productionin normotensives.HLA-DRB1^*04 was also positive related to AT₁-AA production inhypertensives after blood pressure,age and gender adjusted (P=0.07,OR 1.629,95% CI0.954-2.780).Conclsions:These results suggest a difference in the immunogenetic backgroundbetween the positive and negative autoatibodies with hypertension or normotension.Theblood pressure and HLA-DRB1^*04 allele increased the risk for AT₁-AA production.Partâ…¢Association about Angiotensinâ…¡Receptor GenePolymorphism,AT₁-receptor autoantibody production,and BloodPressure Response to CandesartanBackground:The BP response to AT₁ receptor blockers (ARBs) varied markedlyamong individuals and autoantibodies against AT₁ receptor (AT₁-AAs) were important forthe development of hypertension,our purpose was to identify the association betweenanti-AT₁-receptor autoantibody production and angiotensinâ…¡receptor genes (AGTR1)polymorphism,and to study whether they were contributions to the variation in bloodpressure (BP) response to candesartan in essential hypertensive patients.Methods:We random selected 175 essential hypertensive patients and enter an 8weeks clinical trial with candesartan treatment.We genotyped them for 3 SNPs(rs1492078,rs5186 and rs380400) in the AGTR1 genes by direct DNA sequencing. AT₁-AAs were detected by ELISA.Results:The diastolic BP reduction response to candesartan therapy was nosignificant difference between AT₁-AA positive and negative groups.The systolic BPreduction by candesartan was greater in AT₁-AA positive groups (-35.34±17.36 mmHg)than in AT₁-AA negative ones (-28.96±14.82 mmHg),and the difference reachedstatistical significance (P=0.014,adjusted P=0.050).According to the prevalence ofAT₁-AAs,only the haplotype [GAC] was significant association with AT₁-AAs and showedthe protective effect on the AT₁-AA production (adjusted P=0.028 OR 0.342,95% CI0.131-0.890).Meanwhile,SNP rs5186 (A/C) and haplotype [GCC] were significant SBPreduction to Candesartan (adjusted P=0.028 and P=0.026,respectively),and haplotype[AAC] showed a trend toward a greater DBP reduction in response to Candesartan therapy(adjusted P=0.016).Conclusion:AT₁-AA production might partially owe to AGTR1 gene polymorphism.Furthermore,AT₁-AAs and AGTR1 gene polymorphism could solely or jointly affectantihypertensive response to Candesartan.