BACKGROUND Hypertension is seen in 70% of autosomal dominant polycystic kidney disease (ADPKD) patients by the age of 30 prior to decline in kidney function. However, cardiac origins of hypertension, such as the natriuretic peptide signaling pathway, have not been fully investigated. We hypothesized that cardiomyocyte-localized polycystin proteins contribute to production of natriuretic peptides, and loss of this pathway would contribute to hypertension. METHODS Telemetry, echocardiography, and a molecular analysis of the natriuretic peptide pathway from left-ventricular tissue of cardiomyocyte-specific knock-out models of polycystin-2 (cPC2-KO) mice and Cre control littermates was conducted. Complementary studies were conducted in ex-vivo murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 KO of PKD2 and in in-vitro cell lines. RESULTS cPC2-KO mice demonstrated diurnal hypertension. Circulating ANP and BNP were unchanged between cPC2-KO and Cre mice. Analysis of the pathways involved in production, maturation, and activity of natriuretic peptides identified decreased transcription of CgB, PCSK6, NPR1 and NFAT genes in cPC2-KOs. Human iPSC-derived cardiomyocytes with PC2-KO failed to produce ANP. Re-expression of polycystin-2 in a myoblast cell line, but not pathogenic forms of polycystin-2, restored ANP production. CONCLUSIONS Natriuretic peptide production required cardiac localized polycystin-2 and loss of this pathway may contribute to the development of hypertension in ADPKD.

中文翻译：

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利钠肽信号通路中的心脏定位多囊蛋白-2 和高血压。


背景 70% 的常染色体显性遗传性多囊肾病 （ADPKD） 患者在 30 岁之前出现高血压，然后肾功能下降。然而，高血压的心脏起源，例如利钠肽信号通路，尚未得到充分研究。我们假设心肌细胞定位的多囊蛋白有助于利钠肽的产生，而该途径的缺失会导致高血压。方法 对多囊蛋白-2 （cPC2-KO） 小鼠和 Cre 对照同窝小鼠心肌细胞特异性敲除模型的左心室组织利钠肽通路进行遥测、超声心动图和分子分析。在离体小鼠心脏、用人 iPSC 驱动到具有 PKD2 的 CRISPR/Cas9 KO 的心肌细胞的心肌细胞的工程心脏组织和体外细胞系中进行了补充研究。结果 cPC2-KO 小鼠表现出昼夜高血压。cPC2-KO 和 Cre 小鼠的循环 ANP 和 BNP 没有变化。对利钠肽产生、成熟和活性相关途径的分析发现，cPC2-KOs 中 CgB 、 PCSK6 、 NPR1 和 NFAT 基因的转录减少。具有 PC2-KO 的人 iPSC 来源的心肌细胞无法产生 ANP。多囊蛋白-2 在成肌细胞系中的重新表达，而不是多囊蛋白-2 的致病形式，恢复了 ANP 的产生。结论 利钠肽的产生需要心脏定位的多囊蛋白-2，该通路的缺失可能导致 ADPKD 高血压的发生。