Division of Nephrology, Department of Medicine Cheng Hsin General Hospital Taipei Taiwan.
Institute of Clinical Medicine National Yang Ming Chiao Tung University Taipei Taiwan.
J Am Heart Assoc. 2022 Jul 19;11(14):e025208. doi: 10.1161/JAHA.121.025208. Epub 2022 Jul 5.
Background Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease. Corin converts proatrial natriuretic peptide into its active form after being activated by PCSK6 (proprotein convertase subtilisin/kexin type 6) protease. It remains unknown whether the PCSK6/corin/atrial natriuretic peptide pathway plays a role in CKD-induced cardiomyopathy. Methods and Results Serum corin, left ventricular mass index, and corin-left ventricular mass index correlation were compared between outpatients with versus without CKD. Cardiac corin expression and activity as well as serum corin were compared between 5/6 nephrectomy CKD animal models and sham controls. The effects of indoxyl sulfate, a uremic toxin, on cardiomyocytes were examined in vitro in H9c2 cells. A total of 543 patients were enrolled in this study. Serum corin levels were elevated in patients with CKD compared with levels in patients without CKD. Serum corin levels correlated negatively with left ventricular mass index in participants without CKD, but not in patients with CKD. Compared with sham controls, CKD mice had higher serum corin levels and increased cardiac expression of corin but reduced cardiac corin conversion activity. Indoxyl sulfate stimulated corin expression while suppressing serine protease activity in H9c2 cardiomyoblasts. Lower PCSK6 expression in CKD mouse hearts and indoxyl sulfate-treated H9c2 cardiomyoblasts may explain, at least partly, the observed CKD-associated reduction in corin activity. Conclusions In CKD, cardiac and serum levels of corin are increased, yet corin activity is suppressed. The latter may be attributable to reduced PCSK6 expression. These findings suggest that corin dysfunction may play a significant role in the pathogenesis of CKD-associated cardiomyopathy.
慢性肾脏病（CKD）与心血管疾病风险增加相关。在被 PCSK6（脯氨酸羧肽酶/枯草溶菌素蛋白酶 6）蛋白酶激活后，Corin 将前心钠肽转化为其活性形式。PCSK6/corin/心钠肽途径是否在 CKD 诱导的心肌病中起作用尚不清楚。
比较了门诊 CKD 患者与非 CKD 患者的血清 corin、左心室质量指数和 corin-左心室质量指数相关性。比较了 5/6 肾切除 CKD 动物模型与假手术对照的心脏 corin 表达和活性以及血清 corin。在 H9c2 细胞中体外检测尿毒症毒素吲哚硫酸酯对心肌细胞的影响。
共纳入 543 例患者。与非 CKD 患者相比，CKD 患者的血清 corin 水平升高。在无 CKD 的参与者中，血清 corin 水平与左心室质量指数呈负相关，但在 CKD 患者中则无相关性。与假手术对照组相比，CKD 小鼠的血清 corin 水平升高，心脏 corin 表达增加，但心脏 corin 转化活性降低。吲哚硫酸酯刺激 H9c2 心肌细胞中的 corin 表达，同时抑制丝氨酸蛋白酶活性。CKD 小鼠心脏和吲哚硫酸酯处理的 H9c2 心肌细胞中 PCSK6 表达降低可能至少部分解释了观察到的 CKD 相关的 corin 活性降低。
在 CKD 中，心脏和血清中的 corin 水平增加，但 corin 活性受到抑制。后者可能归因于 PCSK6 表达降低。这些发现表明，corin 功能障碍可能在 CKD 相关心肌病的发病机制中起重要作用。
