Cardiac Localized Polycystin-2 plays a Functional Role in Natriuretic Peptide Production and its Absence Contributes to Hypertension

Area of Science:

• Nephrology
• Cardiology
• Genetics

Background:

• Cardiovascular complications are the leading cause of mortality in autosomal dominant polycystic kidney disease (ADPKD).
• Hypertension affects 70% of ADPKD patients by age 30, preceding significant kidney function decline.
• Natriuretic peptides (NPs), like ANP and BNP, regulate sodium and water excretion and are released by cardiomyocytes.

Approach:

• Investigated the role of cardiomyocyte-localized polycystin proteins in NP production using mouse models and engineered heart tissue.
• Generated cardiomyocyte-specific polycystin-2 (PC2) knock-out (cPC2-KO) mice to study diurnal hypertension and NP expression.
• Utilized CRISPR/Cas9 to create PKD2 knock-out human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to assess ANP production.

Key Points:

• Mice heterozygous for Pkd2 and cPC2-KO mice exhibited attenuated NP responses and diurnal hypertension.
• cPC2-KO mice showed decreased ANP and BNP expression in the left ventricle.
• Reduced transcription of CgB, PCSK6, and NFAT genes was observed in cPC2-KOs, impacting NP pathways.
• PKD2-deficient hiPSC-CMs failed to produce ANP, confirming PC2's role in NP synthesis.

Conclusions:

• Cardiomyocyte polycystin-2 (PC2) is crucial for natriuretic peptide (NP) production.
• Absence of cardiac PC2 leads to a hypertensive, volume-expanded phenotype.
• This mechanism may contribute to the development of hypertension in autosomal dominant polycystic kidney disease (ADPKD).