New Study Uncovers a Cardiac Link to Hypertension in Polycystic Kidney Disease

A groundbreaking study published in the Journal of the American Society of Nephrology has uncovered a novel mechanism behind early-onset hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD). The research, led by Dr. Ivana Y. Kuo at Loyola University Chicago, demonstrates that a protein called polycystin-2 (PC2) plays a crucial role in regulating blood pressure through the production of natriuretic peptides in the heart.

Mutations in polycystin-2 (PC2; gene name PKD2), alongside its partner protein polycystin-1 (PC1; PKD1) cause ADPKD, the most common genetic cause of renal failure. There is no cure for ADPKD, a progressive disease wherein one of the first symptoms experienced is hypertension. PC2 is a calcium-permeable ion channel essential for kidney function, cellular signaling, and cardiovascular health. It can regulate calcium homeostasis in the endoplasmic reticulum, plasma membrane, and primary cilia. In kidneys, PC2, in complex with its partner protein PC1, acts as a mechanosensor for fluid flow. PC2 influences cell proliferation, polarity, apoptosis, and autophagy and key signaling pathways like mTOR and Wnt, all pathways which are dysregulated in the formation of kidney cysts. What has been understudied, however, is the etiology of hypertension in ADPKD patients.

The study shows that the absence of cardiac PC2 leads to significantly reduced natriuretic peptide (NP) production, impairing the body’s ability to regulate blood volume and sodium levels. This could explain why nearly 70% of ADPKD patients develop high blood pressure long before their kidneys fail. Natriuretic peptides (ANP, BNP, CNP) are heart-derived hormones that regulate blood pressure and fluid balance by promoting vasodilation, sodium excretion, and diuresis while inhibiting the renin-angiotensin-aldosterone system (RAAS). Clinically, BNP and NT-proBNP serve as key biomarkers for heart failure diagnosis, and natriuretic peptide-targeting drugs like sacubitril/valsartan are used to treat hypertension and cardiovascular diseases.

“Our findings suggest that PC2 in heart cells is involved in producing natriuretic peptides, and its absence predisposes individuals to a hypertensive, volume-expanded state,” said Dr. Kuo, the study’s senior author. “This may contribute significantly to our understanding in the development of hypertension in ADPKD patients.”

A Shift in Understanding Hypertension in ADPKD

ADPKD is a genetic disorder affecting about one in 700 people worldwide. It causes cysts to develop in the kidneys, leading to progressive loss of function. However, cardiovascular disease, not kidney failure, is the leading cause of death in ADPKD patients. While previous research linked ADPKD-related hypertension to overactivation of the renin-angiotensin-aldosterone system (RAAS) and vascular abnormalities, this new study suggests that a primary defect in the heart itself may be a key contributor.

“We found that when PC2 is missing from heart cells, these cells lose their ability to produce natriuretic peptides,” explained Dr. Márquez-Nogueras, one of the study’s first authors. “Without these hormones, the body struggles to excrete excess sodium and water, leading to increased blood volume and hypertension.”

The research team used a variety of sophisticated techniques, including genetically modified mice and human stem cell-derived heart tissues, to demonstrate the link between PC2 and natriuretic peptide production. Using a genetically modified mouse model, the researchers demonstrated that mice lacking cardiac PC2 developed high blood pressure without any signs of kidney disease. Further experiments on human induced pluripotent stem cell-derived cardiomyocytes confirmed that knocking out the PKD2 gene drastically reduced NP production.

“This was a major surprise,” said Dr. Kuo. “Even though these cells were otherwise functioning normally, they simply couldn’t make the natriuretic peptides needed to control blood pressure. That told us PC2 isn’t just another structural protein—it’s actively involved in a critical hormonal pathway.”

Could This Lead to New Treatments?

Currently, hypertension in ADPKD is treated primarily with RAAS inhibitors, such as ACE inhibitors or angiotensin receptor blockers (ARBs). However, these treatments do not address NP deficiency, which could be a major factor driving blood pressure increases in ADPKD patients.

The findings suggest that therapies aimed at restoring natriuretic peptide function, such as neprilysin inhibitors (like sacubitril), might be particularly beneficial for ADPKD patients. Neprilysin inhibitors, which prevent NP breakdown, are already used in heart failure treatment but their effectiveness in ADPKD patients is untested.

“This study opens up an entirely new line of investigation. If NP deficiency is a major driver of early-onset hypertension in ADPKD, then drugs that enhance natriuretic peptide activity could be game changers for these patients”, said Elisabeth DiNello, a co-author of this study, who is now working as a scientist at Marin Biologic Laboratories (Novato, CA).

The team hopes to expand their research to clinical studies in ADPKD patients, examining whether neprilysin inhibitors could provide better blood pressure control than standard RAAS-blocking therapies.

A New Direction for ADPKD Research

Beyond hypertension, this discovery raises broader questions about PC2’s role in cardiac physiology and whether similar defects might contribute to other cardiovascular diseases.

“ADPKD has long been considered a kidney disease, but it’s becoming clear that it’s much more than that,” said Dr. Kuo. “If we can figure out how to correct NP dysfunction in these patients, we might not only improve blood pressure control but also reduce their overall cardiovascular risk.”

With these new insights, the research community now has a fresh perspective on the complex relationship between the kidneys, the heart, and blood pressure regulation. The authors emphasize that more studies are needed to fully translate these findings into clinical practice, but they remain optimistic that this work could lead to better, more targeted treatments for ADPKD-associated hypertension.

Reference

Márquez-Nogueras, Karla M.1; Elliott, Brandon1; Thuo, Paula1; DiNello, Elisabeth1; Knutila, Ryne M.1; Fritzmann, Geena E.1,2; Vuchkovska, Virdjinija1; Flury, Sarah1; Willis, Monte3; Chapman, Arlene B.4; Cao, Quan1,2; Barefield, David Y.1,2; Kuo, Ivana Y.1,2. Cardiac Localized Polycystin-2 in the Natriuretic Peptide Signaling Pathway and Hypertension. Journal of the American Society of Nephrology 36(1):p 34-47, January 2025. | DOI: 10.1681/ASN.0000000000000490

Disclaimer: This information is intended solely for research purposes and does not serve as medical advice.

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