难治性高血压基因与遗传背景课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,难治性高血压,-,基因与遗传背景,惠汝太,加拿大临床科学博士,北京中国医学科学院阜外医院,高血压中心首席专家,国家心脏中心,国家心血管病重点实验室常务副主任,2012-07-07,难治性高血压-基因与遗传背景惠汝太,难治（顽固）性高血压定义,除外近期确诊的高血压、未接受治疗的高血压，,3,个降压药,(,包括一个利尿剂,),，有效剂量、足时（,4-8,周）后，血压仍,140/90,毫米汞柱,或糖尿病、肾病患者仍高于,130/80,毫米汞柱；,为难治性高血压。,近来有人认为：,4,个降压药，血压不达标，可以诊断为难治性高血压。,难治（顽固）性高血压定义除外近期确诊的高血压、未接受治疗的高,高血压,-,复杂原因,高血压-复杂原因,在难治性高血压当中，继发性高血压比我们想象的多；单基因高血压是继发性高血压重要病因之一,三级甲等医院,4429,例难治性高血压中,%,为继发性高血压，,60,岁以上的难治性高血压患者中,17%,为继发性高血压,（,Anderson GH Jr,etal.J Hypertens 1994;12:609,）。,一般估计：继发性高血压患病率,6%-20%,单基因突变导致的高血压：至少,19,个致病基因,导致嗜铬细胞瘤：,9,个,导致盐敏感高血压：,10,个,在难治性高血压当中，继发性高血压比我们想象的多；单基因高血,309,例,16-30,岁（平均,24.05.2,岁）青年难治性高血压住院（,2002-2008,年）患者病因分析,青年顽固性高血压有,40%,能找到原因，解除病因，免得终生服药。,比率,原发性高血压,185,例,59.9%,继发性高血压占,124,例,40.1%,肾动脉性高血压,88,例,28.5%,主动脉缩窄,13,例,4.2%,原醛,9,例,2.9%,肾实质高血压,5,例,1.6%,Liddle,综合征,3,例,1.0%,其他原因,3,例,1.0%,未分类,3,例,1.0%,其他原因：,1,例白大衣高血压，,1,例柯兴氏，,1,例肾素瘤,吴燕，惠汝太等，未发表资料，,2010,309 例16-30岁（平均24.05.2岁）青年难治性高,高血压的遗传度：,40%-60%,，,中国盐敏感高血压,58.7%,；,其中隐藏着导致盐敏感高血压基因变异的贡献？,高血压的遗传度：40%-60%，,目前找到的,19,个高血压致病基因,主要在肾与肾上腺表达,目前多数单基因高血压病因：肾离子通道，肾上腺。,目前找到的19个高血压致病基因目前多数,单基因高血压,肾小管,：,盐皮质类固醇受体（,MR,）基因变异导致怀孕加重,的高血压，糖皮质素抵抗,，,ENaC,（,Liddle,氏综合征,），,WNK4,1,（,Gordon,氏综合征,），,TheWNK4gene encodes a serine-threonine,（丝氨酸,-,苏氨酸）,kinase expressed in distal nephron,肾上腺：皮质,：,GRA,，,11HSD2,（,AME,）,肾上腺增生,髓质：嗜铬细胞瘤,20%,单基因高血压肾小管：盐皮质类固醇受体（MR）基因变异导致怀孕,盐皮质激素受体活性突变 亦称为妊娠加重的高血压,为常染色体显性遗传疾病，,2000,年,Geller,等首次报道盐,皮质激素受体（,MR,）的配体,结合域发生突变，第,810,位,丝氨酸被亮氨酸取代,(S810L),，使受体的,第,5,螺旋,和第,3,螺旋间发生分子交互,作用，构象发生改变，导致,该突变受体在无配体结合时,也处于半激活状态,(,活性增,加,25%,左右,),。,而生理状态下的,MR,拮抗剂如螺内酯和孕酮、以及生理状态下不能结合和激活,MR,的皮质酮，也可结合并激活突变的盐皮质激素受体。怀孕后体内孕酮可升高,100,倍，因而妊娠后,MR,突变携带者高血压加重恶化。螺内酯治疗会加重高血压。,盐皮质激素受体活性突变 亦称为妊娠加重的高血压为常染色体显性,Role of the KS-WNK1 isoform in renal physiology,Mutations in the WNK1 and WNK4 genes,encoding members of the WNK(With No lysine(K)family of serine-threonine kinases,are responsible for Familial Hyperkalemic Hypertension(FHHt),a rare form of human arterial hypertension characterized not only by hyperkalemia and hypertension but also by a hyperchloremic metabolic acidosis.,As expected,NCC expression and phosphorylation were increased in KS-WNK1-/-mice.Na+and K+balance was affected as evidenced by increased diastolic blood pressure,decreased urinary aldosterone level and modified K+channels expression.The surprising result was the absence of metabolic disturbance under several regimen despite increased NCC activity,which was explained in part by a counterdownregulation of ENaC expression.(Hadchouel et al.Proc Natl Acad Sci U S A.2010).,Role of the KS-WNK1 isoform in,Pseudohypoaldosteronism,PHA-II,（,Gordon syndrome,）,is a rare familial renal tubular defect characterized by,hypertension,and,hyperkalemic metabolic acidosis,in the presence,of low renin and aldosterone levels,.,机制：,renal tubular unresponsiveness or resistance to the action of aldosterone.,Volume depletion or hypervolemia;renal salt wasting or retention;hypotension or,hypertension,PseudohypoaldosteronismPHA-II（,PHA-I,itself has been recognized as a heterogeneous syndrome that includes at least 2 clinically distinguishable entities with either renal or multiple target organ defects(MTOD).,Early childhood,hyperkalemia,or renal tubular acidosis,(RTA)type IV subtype 5,is a variant of the renal form of PHA-I.,PHA-I itself has been recogniz,难治性高血压基因与遗传背景课件,microRNAs as new partners for WNK1 expression influenced by Na+,K+regimen,two kidney-specific microRNAS,miR-192,and,miR-215,that target sequence in the 3UTR of the gene.In vitro assays showed that miR-192,but not miR-215,is able to regulate WNK1 expression at the post-transcriptional level only.,miR-192 expression is strongly inhibited by Na+depletion,K+loading and aldosterone infusion.In addition,L-WNK1 expression,while unaffected by any of the conditions at the RNA level,was increased at the post-transcriptional level by aldosterone and confirmed that KS-WNK1 transcripts level was increased by K+loading and aldosterone.,Taken together,these results suggest that down-regulation of miR-192 could be involved in the stimulation of WNK1 expression by aldosterone in the kidney.,A new working hypothesis under which microRNAs could play a role in the regulation of ion transport in the kidney(Elvira-Matelot et al.J Am Soc Nephrol.2010).,microRNAs as new partners for,拟盐皮质激素增多症（,AME,）,本病为常染色体隐性遗传疾病。,人体内糖皮质激素,(,皮质醇,),和醛固酮对盐皮质激素受体具有同样的亲和性，生理情况下体内循环中皮质醇比醛固酮高,1000,倍，但由于肾脏内存在,11-,羟类固醇脱氢酶,型,(11-HSD),，可将皮质醇转化生成不能激活盐皮质激素受体的皮质酮，因此盐皮质激素受体不会被糖皮质激素激活。,HSD11B,基因位于,16q22,，该基因发生突变可导致,11-HSD,酶无活性或活性降低，大量皮质醇不能被转化成皮质酮,，,大量蓄积的皮质醇占据远端肾小管的盐皮质激素受体，激活转录因子及血清糖皮质类固醇激酶，使泛素连酶,Nedd4-2,磷酸化，磷酸化的,Nedd4-2,不能与,ENaC,结合进而灭活,ENaC,，导致,ENaC,活性升高，钠重吸收增加，出现类似醛固酮增高的临床表现,高血压和低血钾，即称类盐皮质激素增多症,(AME),。,HSD11B,基因突变不仅导致基因表达降低或对底物的亲和力降低，也可导致,11-HSD,蛋白酶的稳定性降低，半衰期显著缩短。,拟盐皮质激素增多症（AME）本病为常染色体隐性遗传疾病。大量,Recessive and dominant,KLHL3,mutations in PHAII kindreds,Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities,Nature482,98102(02 February 2012)doi:10.1038/nature10814,Rece