Mechanisms driving cardiac dysfunction in Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病心脏功能障碍的驱动机制

• 批准号: 10443441
• 负责人: Francisco Altamirano
• 金额: $ 40.38万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443441
• 关键词: Ablation; Action Potentials; Affect; Age; Alleles; Automobile Driving; Autosomal Dominant Polycystic Kidney; Biochemical; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cells; Clinical; Complement; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dose; Economic Burden; Electrophysiology (science); Event; Exhibits; Functional disorder; Gene Mutation; Genes; Heart; Heart Diseases; Heart failure; Hereditary Disease; Histologic; Human; Hypertension; Impairment; In Vitro; Individual; Intervention; Kidney; Kidney Diseases; Kidney Failure; Knock-in; Kv channel-interacting protein 2; Left; Longevity; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Myocardial dysfunction; NG-Nitroarginine Methyl Ester; Pathway interactions; Patients; Persons; Pharmacology; Potassium; Potassium Channel; Predisposition; Process; Proteins; Quality of life; Regulation; Reporting; Role; Sarcoplasmic Reticulum; Signal Transduction; Techniques; Testing; Time; Ventricular; Ventricular Dysfunction; base; comorbidity; defined contribution; health care economics; heart function; improved; in vivo; induced pluripotent stem cell derived cardiomyocytes; insight; kidney cell; kidney dysfunction; knock-down; mortality; mouse model; mutant; novel; overexpression; phospholamban; polycystic kidney disease 1 protein; renal epithelium; sarcoplasmic reticulum calcium ATPase; small molecule

Cardiovascular disease is a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Characterized by progressive renal dysfunction, ADPKD imposes very significant healthcare and economic burdens. It has commonly been assumed that progressive renal impairment promotes cardiac disease; however, our preliminary data suggest that cardiac dysfunction originates in cardiomyocytes and manifests prior to renal failure in ADPKD. Recent clinical evidence supports our findings by showing that ADPKD patients exhibit ventricular dysfunction before the onset of renal failure, even in non-hypertensive individuals. Mutations in the gene encoding Polycystin-1 (PC1) occur in 85% of patients and are responsible for the most severe cases. Importantly, PC1 is expressed in cardiomyocytes, yet its role(s) there is(are) poorly understood. We propose that the mutant PC1 – in a cardiomyocyte-autonomous fashion – initiates and drives heart disease in ADPKD, independent of renal failure. Our data show that PC1 cardiomyocyte-specific deletion promotes systolic and diastolic dysfunction in mice. Furthermore, using a mouse model harboring a clinically established ADPKD-causing PC1 mutation (RC allele), we provide evidence of impaired calcium-cycling and contractility at the cardiomyocyte level, which occur before the onset of renal failure. Heterozygous RC/+ young mice manifest alterations in calcium handling/contractility in isolated cardiomyocytes, which correlate with reduced left ventricular global longitudinal strain and diastolic dysfunction. We discovered that PC1 regulates action potential duration via Kv channel current regulation. PC1 ablation shortens action potential duration and impairs both calcium transients and contractility in cardiomyocytes. Additionally, PC1 deletion impairs sarcoplasmic reticulum (SR) calcium loading through reduced SR calcium-ATPase (SERCA) activity. These data have led us to hypothesize that ADPKD-causing PC1 mutations disrupt PC1 actions in cardiomyocytes, impair cardiac function and predispose the heart to hypertension-induced heart failure, independent of renal dysfunction. To test this hypothesis, we propose three aims: 1) determine how PC1 mutations affect action potentials and Kv channel activity and impinge on calcium handling and contractility. 2) elucidate mechanisms whereby PC1 regulates SR calcium loading and SERCA to maintain cardiomyocyte function and test the impact of ADPKD mutations in PC1 on these events. 3) determine in vivo whether alterations in PC1 signaling in cardiomyocytes drive cardiac dysfunction and predispose the heart to hypertension-induced heart failure. Completion of our studies will provide paradigm-shifting information regarding the role of cardiomyocyte-autonomous events driving heart disease in ADPKD, the leading cause of death in these patients.

心血管疾病是常染色体显性遗传性多囊肾病(ADPKD)患者发病和死亡的主要原因。以进行性肾功能障碍为特征的ADPKD会造成非常严重的医疗和经济负担。一般认为进行性肾损害促进心脏疾病；然而，我们的初步数据表明，心功能障碍起源于心肌细胞，在ADPKD中表现为肾功能衰竭之前。最近的临床证据支持我们的发现，表明ADPKD患者在肾功能衰竭发作之前就表现出心功能不全，即使在非高血压患者中也是如此。编码多囊蛋白-1(PC1)的基因突变发生在85%的患者中，并导致最严重的病例。重要的是，PC1在心肌细胞中表达，但其作用(S)却知之甚少。我们认为，突变的PC1-以心肌细胞自主的方式-在ADPKD中启动和驱动心脏病，独立于肾功能衰竭。我们的数据显示，PC1心肌细胞特异性缺失促进了小鼠的收缩和舒张期功能障碍。此外，利用临床已证实的ADPKD导致PC1突变(RC等位基因)的小鼠模型，我们提供了心肌细胞水平的钙循环和收缩能力受损的证据，这发生在肾功能衰竭发生之前。杂合子RC/+幼鼠在分离的心肌细胞中表现出钙处理/收缩能力的改变，这与左心室整体纵向应变减少和舒张期功能障碍有关。我们发现PC1通过Kv通道电流调节来调节动作电位时程。PC1消融可缩短心肌细胞动作电位时程，损害心肌细胞的钙瞬变和收缩能力。此外，PC1缺失通过降低肌浆网钙-ATPase(SERCA)活性来损害肌浆网(SR)钙负荷。这些数据使我们假设，ADPKD导致的PC1突变扰乱了心肌细胞的PC1活动，损害了心功能，使心脏容易患上高血压引起的心力衰竭，而不是肾功能障碍。为了验证这一假设，我们提出了三个目标：1)确定PC1突变如何影响动作电位和Kv通道活动，以及如何影响钙离子的处理和收缩。2)阐明PC1调节肌浆网钙负荷和SERCA维持心肌细胞功能的机制，并检测PC1中ADPKD突变对这些事件的影响。3)在体内确定心肌细胞PC1信号的改变是否会导致心功能不全，并使心脏易患高血压所致的心力衰竭。我们研究的完成将提供有关心肌细胞自主事件在ADPKD中驱动心脏病的作用的范式转换信息，ADPKD是这些患者的主要死亡原因。