Counter regulatory mechanisms of cardiotonic steroids in cardio-renal syndrome

项目摘要 慢性肾脏病（CKD）患者通常会发展为“尿毒症性”心肌病，其特征在于舒张功能不全。 功能障碍，左心室肥大和心脏重塑，尽管当代治疗， 神经激素阻滞我们已经描述了强心类固醇（CTS）在 在肾损伤后激活促炎和促纤维化途径， 心肌病CTS是类固醇激素家族，包括蟾蜍二烯内酯，如海蟾蜍精和海蟾蜍精。 在体积膨胀的情况下，例如CKD，端脂蟾毒精显著升高， 通过Na+/K+-ATP酶结合和信号传导导致炎症和心脏纤维化。 对氧磷酶（PON）是水解内酯酶，其取决于同种型，或者在细胞中产生， 肝和循环结合高密度脂蛋白或在组织水平细胞内表达。我们 初步的实验和临床数据表明内酯酶活性降低 CKD患者PON与心脏疾病严重程度和进展的关系。然而潜在的心脏保护作用 机制在很大程度上未知。现在，我们第一次发现了新的机械相互作用 对氧磷酶和内源性CTS之间的关系。有趣的是，PON的内酯酶活性水解CTS， 它们的开环形式与天然CTS不同，不能刺激胶原蛋白形成。所以 本提案的总体目标是检验PON的心脏保护作用可以阻止进行性心脏病的假设。 慢性肾脏病中的纤维化和舒张功能障碍，其机制是通过调节致病性 由内源性CTS诱导的途径。我们的研究将定义一种新的内源性PON底物， 首次建立了CTS活性在减轻心脏重塑中的反调节机制 肾损伤后。

PROJECT SUMMARY Patients with chronic kidney disease (CKD) often develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, left ventricular hypertrophy, and cardiac remodeling, despite contemporary therapies of neurohormonal blockade. We have described a central mechanistic role of cardiotonic steroids (CTS) in activating pro-inflammatory and pro-fibrotic pathways following renal insult that potentiate this uremic cardiomyopathy. CTS are a family of steroid hormones including bufadienolides such as marinobufagenin and telocinobufagin which are significantly elevated in volume expanded conditions such as CKD and can directly lead to inflammation and cardiac fibrosis upon binding and signaling through the Na+/K+-ATPase. Paraoxonases (PON) are hydrolytic lactonase enzymes that, depending on isoform, are either generated in the liver and circulate bound to high-density lipoprotein or are expressed intracellularly at the tissue level. Our preliminary experimental and clinical data demonstrate an association between diminished lactonase activities of PON and cardiac disease severity and progression in CKD. Yet the underlying cardioprotective mechanism(s) are largely unknown. Now, for the first time, we have identified novel mechanistic interactions between paraoxonases and endogenous CTS. Interestingly, the lactonase activities of PON hydrolyze CTS to their open-ring forms which, unlike native CTS, are incapable of stimulating collagen formation. Hence, the overall goal of this proposal is to test the hypotheses that cardioprotection by PON can deter progressive cardiac fibrosis and diastolic dysfunction in CKD, and that the mechanism occurs via modulation of pathogenetic pathways induced by endogenous CTS. Our studies will define a novel endogenous substrate for PON and establish for the first time a counter-regulatory mechanism of CTS activities in attenuating cardiac remodeling following renal insult.