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多囊肾病（ADPKD）患者发病和死亡的主要原因。 ADPKD 的特点是进行性肾功能障碍，造成非常严重的医疗保健和经济负担。人们普遍认为进行性肾功能损害会促进心脏病。然而，我们的初步数据表明，心功能障碍起源于心肌细胞，并在 ADPKD 肾功能衰竭之前出现。最近的临床证据支持我们的发现，表明 ADPKD 患者在肾衰竭发作之前表现出心室功能障碍，即使在非高血压个体中也是如此。 85% 的患者会发生编码多囊蛋白-1 (PC1) 的基因突变，这是导致最严重病例的原因。重要的是，PC1 在心肌细胞中表达，但人们对它的作用知之甚少。我们认为，突变的 PC1 以心肌细胞自主的方式引发并驱动 ADPKD 中的心脏病，与肾功能衰竭无关。我们的数据表明，PC1 心肌细胞特异性缺失会促进小鼠的收缩和舒张功能障碍。此外，使用具有临床上确定的 ADPKD 引起的 PC1 突变（RC 等位基因）的小鼠模型，我们提供了心肌细胞水平钙循环和收缩力受损的证据，这些损伤发生在肾衰竭发作之前。杂合子 RC/+ 年轻小鼠表现出离体心肌细胞钙处理/收缩力的改变，这与左心室整体纵向应变和舒张功能障碍的减少相关。我们发现 PC1 通过 Kv 通道电流调节来调节动作电位持续时间。 PC1 消融会缩短动作电位持续时间并损害心肌细胞的钙瞬变和收缩性。此外，PC1 缺失会通过降低 SR 钙-ATP 酶 (SERCA) 活性来损害肌浆网 (SR) 钙负荷。这些数据使我们推测，引起 ADPKD 的 PC1 突变会破坏心肌细胞中 PC1 的作用，损害心脏功能，并使心脏易于患上高血压引起的心力衰竭，而与肾功能障碍无关。为了检验这一假设，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 通道活性以及如何影响钙处理和收缩性。 2）阐明PC1调节SR钙负荷和SERCA以维持心肌细胞功能的机制，并测试PC1中ADPKD突变对这些事件的影响。 3) 体内确定心肌细胞中 PC1 信号传导的改变是否会导致心脏功能障碍并使心脏易患高血压引起的心力衰竭。我们研究的完成将提供关于心肌细胞自主事件在 ADPKD 中驱动心脏病的作用的范式转变信息，ADPKD 是这些患者的主要死亡原因。