Márquez-Nogueras Karla M, Elliott Brandon, Thuo Paula, DiNello Elisabeth, Knutila Ryne M, Fritzmann Geena E, Vuchkovska Virdjinija, Flury Sarah, Willis Monte, Chapman Arlene B, Cao Quan, Barefield David Y, Kuo Ivana Y
Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.
Stritch School of Medicine, Cardiovascular Research Institute, Loyola University Chicago, Maywood, Illinois.
J Am Soc Nephrol. 2025 Jan 1;36(1):34-47. doi: 10.1681/ASN.0000000000000490. Epub 2024 Sep 20.
Cardiac localized polycystin facilitates natriuretic peptide signaling pathways. Hypertension associated with autosomal dominant polycystic kidney disease may arise from impaired cardiac natriuretic peptide signaling.
Hypertension is seen in 70% of patients with autosomal dominant polycystic kidney disease by age of 30 years before 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.
Telemetry, echocardiography, and a molecular analysis of the natriuretic peptide pathway from left ventricular tissue of cardiomyocyte specific knockout models of polycystin-2 (cPC2-KO) mice and Cre control littermates were conducted. Complementary studies were conducted in murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 knockout of and in cell lines.
cPC2-KO mice demonstrated diurnal hypertension. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide 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 chromogranin B, 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.
Natriuretic peptide production required cardiac localized polycystin-2, and loss of this pathway may contribute to the development of hypertension in autosomal dominant polycystic kidney disease.
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心脏局部的多囊蛋白促进利钠肽信号通路。与常染色体显性多囊肾病相关的高血压可能源于心脏利钠肽信号受损。
在常染色体显性多囊肾病患者中，70%在30岁时出现高血压，此时肾功能尚未下降。然而，高血压的心脏起源，如利钠肽信号通路，尚未得到充分研究。我们推测心肌细胞局部的多囊蛋白有助于利钠肽的产生，而该通路的缺失会导致高血压。
对多囊蛋白-2心肌细胞特异性敲除模型（cPC2-KO）小鼠和Cre对照同窝小鼠的左心室组织进行遥测、超声心动图检查以及利钠肽通路的分子分析。在小鼠心脏、用CRISPR/Cas9敲除 后由人诱导多能干细胞分化为心肌细胞的工程心脏组织以及 细胞系中进行了补充研究。
cPC2-KO小鼠表现出昼夜高血压。cPC2-KO小鼠和Cre小鼠之间循环心房利钠肽（ANP）和脑利钠肽没有变化。对利钠肽产生、成熟和活性所涉及的通路分析发现，cPC2-KO小鼠中嗜铬粒蛋白B、PCSK6、NPR1和NFAT基因的转录减少。PC2-KO的人诱导多能干细胞衍生的心肌细胞未能产生ANP。在成肌细胞系中重新表达多囊蛋白-2，但不是多囊蛋白-2的致病形式，可恢复ANP的产生。
利钠肽的产生需要心脏局部的多囊蛋白-2，该通路的缺失可能导致常染色体显性多囊肾病中高血压的发生。
