Khoury Emad E, Fokra Ahmad, Kinaneh Safa, Knaney Yara, Aronson Doron, Abassi Zaid
Department of Physiology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Department of Cardiology, Rambam Health Care Campus, Haifa, Israel.
Front Physiol. 2021 Oct 18;12:673497. doi: 10.3389/fphys.2021.673497. eCollection 2021.
Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention. However, its pathogenesis remains largely unclarified. Corin, a cardiac serine protease, is responsible for converting proANP and proBNP to biologically active peptides. Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and proprotein convertase subtilisin/kexin-6 (PCSK6), a key enzyme in the conversion of procorin to corin, has not been studied simultaneously in the cardiac and renal tissues in cardiorenal syndrome. Thus, this study aims to examine the status of PCSK6/corin in the cardiac and renal tissues of rats with CHF induced by the creation of aorto-caval fistula (ACF). We divided rats with ACF into two subgroups based on the pattern of their urinary sodium excretion, namely, compensated and decompensated. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more profound in the decompensated subgroup. Corin immunoreactive peptides were detected in all heart chambers at the myocyte membranal and cytosolic localization and in the renal tissue, especially in the apical membrane of the proximal tubule, mTAL, and the collecting duct. Interestingly, the expression and abundance of corin in both the cardiac ventricles and renal tissues were significantly increased in compensated animals as compared with the decompensated state. Noteworthy, the abundance of PCSK6 in these tissues followed a similar pattern as corin. In contrast, furin expression was upregulated in the cardiac and renal tissues in correlation with CHF severity. We hypothesize that the obtained upregulation of cardiac and renal PCSK6/corin in rats with compensated CHF may represent a compensatory response aiming at maintaining normal Na balance, whereas the decline in these two enzymes may contribute to the pathogenesis of avid sodium retention, cardiac hypertrophy, and blunted atrial natriuretic peptide/brain natriuretic peptide actions in decompensated CHF.
充血性心力衰竭（CHF）常导致进行性心脏肥大和盐/水潴留。然而，其发病机制在很大程度上仍不清楚。Corin是一种心脏丝氨酸蛋白酶，负责将proANP和proBNP转化为生物活性肽。尽管对Corin在心脏肥大和心力衰竭中的作用进行了广泛研究，但在心肾综合征的心脏和肾脏组织中，尚未同时研究Corin和前蛋白转化酶枯草杆菌蛋白酶/kexin-6（PCSK6，将前Corin转化为Corin的关键酶）的变化。因此，本研究旨在检测主动脉-腔静脉瘘（ACF）诱导的CHF大鼠心脏和肾脏组织中PCSK6/Corin的状态。我们根据尿钠排泄模式将ACF大鼠分为两个亚组，即代偿组和失代偿组。ACF的建立导致心脏肥大、肺充血和肾功能障碍，在失代偿亚组中更为严重。在所有心腔的心肌细胞膜和细胞质定位以及肾脏组织中均检测到Corin免疫反应性肽，尤其是在近端小管、髓袢升支粗段和集合管的顶端膜中。有趣的是，与失代偿状态相比，代偿动物的心室和肾脏组织中Corin的表达和丰度均显著增加。值得注意的是，这些组织中PCSK6的丰度与Corin的模式相似。相反，弗林蛋白酶的表达与CHF严重程度相关，在心脏和肾脏组织中上调。我们推测，代偿性CHF大鼠心脏和肾脏PCSK6/Corin的上调可能代表一种旨在维持正常钠平衡的代偿反应，而这两种酶的下降可能导致失代偿性CHF中钠潴留、心脏肥大和心房利钠肽/脑利钠肽作用减弱的发病机制。
