Polycystin-1 and Cardiac Remodeling: From Mechanotransduction to Clinical Consequences

Abstract

Polycystin-1 (PC1), traditionally viewed through the lens of renal pathophysiology in autosomal dominant polycystic kidney disease (ADPKD), has emerged as a central regulator of cardiovascular mechanobiology. Recent structural elucidation of the PC1/PC2 complex provides a molecular framework emphasizing its mechanically sensitive ectodomain, regulated proteolytic cleavage, and functional coupling with PC2, framing PC1 as a versatile integrator of biomechanical cues, extracellular matrix interactions, and Ca²⁺ signaling across cardiovascular cell types.

This review synthesizes evidence demonstrating that PC1 plays a direct and primary role in the cardiovascular system, independent of renal decline, regulating vascular homeostasis, endothelial shear stress responsiveness, smooth muscle phenotype, and myocardial mechanotransduction. We describe the molecular mechanisms whereby PC1 dysfunction perturbs nitric oxide signaling, cytoskeletal remodeling, excitation–contraction coupling, and hypertrophic transcriptional programs, and highlight tissue-specific roles in cardiac morphogenesis and adult myocardial integrity.

By integrating structural biology with cardiovascular physiology, this review provides a unified framework for understanding PC1 as a master mechanosensor linking biomechanical forces to pathological remodeling. Critical knowledge gaps, emerging therapeutic opportunities, and the potential role of artificial intelligence in PC1-targeted drug discovery are also discussed.

1. Introduction

The genes PKD1 and PKD2 encode the large transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively¹. Identified approximately three decades ago^2,3 as the genes mutated in autosomal dominant polycystic kidney disease (ADPKD), polycystin dysfunction underlies one of the most clinically significant inherited kidney disorders. ADPKD is characterized by loss of renal epithelial cell polarity and uncontrolled proliferation, culminating in the progressive development of fluid-filled cysts that displace and destroy functional renal parenchyma. The disease arises from germline loss-of-function mutations in either PKD1 (the predominant cause) or PKD2, followed by somatic inactivation of the remaining allele — a two-hit mechanism that accounts for the sporadic distribution of cysts and the typically delayed onset of symptoms. Notably, ADPKD is among the first conditions attributed to loss-of-function mutations in mechanosensitive ion channels⁴. Both genes are essential for embryonic development, as complete loss of either is lethal in mouse models, producing severe renal and pancreatic cysts alongside cardiac defects. At the molecular level, polycystin dysfunction reduces cytosolic calcium (Ca²⁺), disrupting the balance between adenylyl cyclase and phosphodiesterases and driving intracellular cAMP accumulation. Elevated cAMP acts as a dual pathogenic trigger, simultaneously promoting tubular epithelial cell proliferation and activating CFTR (cystic fibrosis transmembrane conductance regulator)-mediated fluid secretion — both essential drivers of cyst expansion⁵.

Polycystins are ubiquitously expressed across diverse cell types, including endothelial cells, vascular smooth muscle cells (VSMCs), cardiomyocytes, and fibroblasts⁶, prompting studies that confirmed a primary role for PC1/PC2 dysfunction in the vascular and cardiac manifestations of ADPKD. In this review, we focus on PC1 and its cardiovascular relevance from physiological and pathophysiological perspectives. Despite significant advances in polycystin structural biology, their precise physiological roles and the mechanisms whereby their loss triggers cyst formation remain incompletely understood.

2. Polycystin-1: Localization, Structure, and Function

2.1. Tissue and Cellular Localization

Early immunolocalization studies identified PC1 and PC2 in various tissues, including endocrine and pancreatic tissues^7,8, though generating specific anti-PC1 antibodies proved challenging, with several early reagents exhibiting non-specific staining confirmed by their persistence in PKD1-knockout models^9–11. Transcriptomic profiling has since confirmed the virtually ubiquitous expression of PC1 and PC2 across multiple cell types^12–14, including VSMCs and endothelial cells of both blood and lymphatic vasculature^15,16. PC1 is also highly expressed in hepatocytes, bile duct epithelia, and pancreatic ductal cells, consistent with the extra-renal manifestations of ADPKD^9,17. Protein-tagging studies further revealed that the lung maintains the highest PC1 expression in adult animals, whereas renal expression declines after the neonatal period¹⁸. PC1 is additionally expressed in the central nervous system — particularly in ependymal and choroid plexus cilia, where its loss is linked to hydrocephalus¹⁹ — as well as in cardiac and skeletal muscle, bone, and adipocytes^18,20. This broad distribution presents a compelling paradox: despite ubiquitous polycystin expression, the clinical phenotype of ADPKD remains predominantly renal.

At the subcellular level, PC1 was initially identified at adherens junctions, desmosomes, and focal adhesions²¹, with subsequent evidence supporting additional plasma membrane localization²². PC2, by contrast, is predominantly found in the endoplasmic reticulum, where it mediates Ca²⁺ efflux^23,24. Heterologous expression studies demonstrated that overexpression of either protein can promote plasma membrane localization of its counterpart, though this interdependency was not universally confirmed²⁵. Notably, ciliary co-localization of PC1 and PC2 has been consistently reported across multiple cell types and tissues^26–28. Figure 1 summarizes the timeline of key polycystin discoveries.

Figure 1.

Timeline of Key Discoveries in Polycystins Research.

2.2. Structure and Function

Sequence and structural analyses classify polycystins into two distinct channel subunit families: PC1-related subunits (PKD1, PKD1L1, PKD1L2, PKD1L3, and PKDREJ), which feature 11 transmembrane (TM) domains (S1–S11) with properties shared between ion channels and adhesion G protein–coupled receptors (aGPCRs); and PC2-related subunits (PKD2, PKD2L1, and PKD2L2), which contain six TM domains (S1–S6) and belong to the transient receptor potential (TRP) channel family^29,30.

Early reports proposed that PC1 and PC2 assemble into a Ca²⁺-permeable channel at the plasma membrane²⁵. However, subsequent studies using siRNA silencing and conditional Pkd1 knockout models challenged this view, suggesting instead that PC2 may function independently as a low-Ca²⁺-permeability cation permeability^31,32. Similarly, whereas early evidence implicated the ciliary PC1/PC2 complex in shear stress sensing^33–35, later work provided conflicting data on its role as a Ca²⁺-responsive mechanosensor³⁶. A subsequent cryo-electron microscopy (cryo-EM) study resolved the high-resolution structure of the PC1/PC2 complex, demonstrating that both proteins assemble into a pore-forming channel with 1:3 stoichiometry^30,37–39. Importantly, this structural model excluded the PC1 N-terminal fragment (NTF) and C-terminal tail (CTT), leaving the functional roles of these domains unresolved. Nevertheless, the transmembrane domain organization revealed that PC1–PC2 interaction occurs not only through the intracellular coiled-coil–containing COOH-terminal tail, but also directly via the transmembrane domains, corroborating the formation of a functional channel complex³⁰.

2.2.1. Primary Structure of PC1:

PC1 is a large transmembrane protein of 4,302 amino acids, with a predicted molecular mass of 462 kDa and an apparent mass of ~520 kDa attributable to extensive glycosylation. Its architecture comprises a large extracellular NH₂-terminal region (3,072 amino acids), 11 TM domains, and a short intracellular CTT of 198 amino acids. The NH₂-terminal ectodomain harbors multiple structural domains, including leucine-rich repeats (LRR), a wall integrity and stress response component (WSC), a C-type lectin domain (CTL), a low-density lipoprotein-like (LDL-A) domain, 16 immunoglobulin-like polycystic kidney disease (PKD) repeats, and a ~1,000-amino-acid Receptor for Egg Jelly (REJ) region⁴⁰ — the latter incorporating fibronectin type III (FNIII) repeat motifs⁴¹. The extensibility of these NH₂-terminal domains, particularly the PKD and FNIII repeats, supports a mechanosensory function for PC1^42,43. Immediately downstream, a G protein–coupled receptor proteolytic site (GPS) mediates autoproteolytic cleavage and release of the N-terminal fragment⁴⁴. Beyond the GPS site, the 11 TM domains are separated by five intracellular and five extracellular loops; the first intracellular loop harbors a lipoxygenase and α-toxin (PLAT) domain involved in lipid binding, and the third extracellular loop harbors a tetragonal opening for polycystins (TOP) domain — homologous to that of PC2 and essential for channel gating. The CTT encompasses a coiled-coil domain, a putative G-protein–binding site, two polyproline motifs (one capable of SH3 domain interaction), and predicted nuclear and mitochondrial localization signals^45,46. Figure 2 summarizes the structure of PC1.

Figure 2.

A) Structural features of Polycystin-1 (PC1). B) C-terminal cleavage fragments: p100, CTT, and p17.

2.2.2. N- and C-terminal Cleavage:

PC1 undergoes multiple proteolytic cleavages affecting both its extracellular NH₂-terminal domain and its cytoplasmic CTT⁴⁷. The primary N-terminal cleavage occurs at a conserved GPS motif immediately adjacent to the first TM domain, whereas subsequent CTT cleavages release soluble fragments that translocate to the nucleus and mitochondria to influence local signaling⁴⁴.

2.2.2.1. N-terminal Cleavage:

GPS cleavage is a fundamental post-translational event in PC1 biogenesis, trafficking, and function in vivo^45,48. This autoproteolysis is mediated by the GAIN (GPCR autoproteolysis inducer) domain — a feature shared exclusively with adhesion GPCRs — which catalyzes peptide bond hydrolysis at the GPS near (TM1)^49–51, generating an NTF and a multi-TM core⁴⁵. Whereas the NTF may function as a mechanosensor, the precise role of the multi-TM core remains to be established. Although GPS mutations cause renal cyst formation, the full functional consequences of this autoproteolytic event remain poorly understood⁴⁸. Notably, Ha et al. demonstrated that a soluble fragment derived from the PC1 N-terminal ectodomain functions as an intrinsic agonist necessary and sufficient for polycystin channel activation⁵², suggesting a novel autoregulatory mechanism.

2.2.2.2. C-terminal Cleavage:

Beyond GPS cleavage, the PC1 C-terminal fragment (CTF) — which extends into the cytoplasm from the eleventh TM domain and is integral to downstream signaling^48,53 — undergoes further proteolytic processing, generating three distinct fragments: the CTT, p17, and p100⁵³. The enzymes mediating these cleavages remain largely unidentified⁵⁴.

The CTT (~30–35 kDa), first detected in vivo in mouse kidney tissue following mechanical stimulation, accumulates in the nucleus where it regulates transcriptional programs⁵⁴. The polycystin complex also functions as an oxygen sensor with cellular oxygen tension regulating its subcellular topology and activity through interaction with the prolyl hydroxylase EGLN3⁵⁵; accordingly, PKD1 downregulation reduces oxygen consumption and attenuates mitochondrial Ca²⁺ uptake following bradykinin-induced ER calcium release⁵⁵. The CTT fragment additionally translocates to the mitochondrial matrix⁵⁶, and PKD1^−/− renal epithelial cells exhibit impaired fatty acid utilization and mitochondrial morphological abnormalities also observed in ADPKD patient kidneys⁵⁶, collectively implicating PC1 as a regulator of mitochondrial function through ER–mitochondria Ca²⁺ coordination. The cleavage site generating the CTT remains unresolved: whereas Merrick et al. proposed involvement of the intramembrane protease γ-secretase⁵⁷, Lin et al. failed to confirm this⁵⁶, highlighting a critical gap in understanding PC1 processing.

The p17 fragment (~17 kDa, comprising the final 112 amino acids) interacts with the transcriptional activators STAT3 and STAT6⁵⁸ and the co-activator p100⁵⁹, and appears to be generated in response to reduced tubular fluid flow^59–61, though the underlying mechanism remains unknown. The p100 fragment, generated by cleavage within the third intracellular loop, retains the last six TM domains and the carboxy-terminal region, yielding a truncated integral membrane protein⁶². Localizing to the ER, p100 interacts with STIM1 — an ER-resident Ca²⁺ sensor⁶² — supporting a role in cellular Ca²⁺ homeostasis. The relationship between these cleavage products and the broader polycystin signaling network remains to be determined.

3. Role of PC1 in Cardiac Development

Converging evidence supports a role for PC1 in cardiac development. Mice harboring a targeted Pkd1^{del17–21βgeo−/−} mutation die at embryonic stages with significant cardiac defects, including myocardial disorganization, double outlet right ventricle, and abnormal atrioventricular septation, along with skeletal and renal abnormalities⁶³. Clinically, analysis of Mayo Clinic records (1993–2020) revealed increased frequency of hereditary heart disease in ADPKD patients compared with the general population⁶⁴, as well as a higher incidence (1984–2015) of cardiomyopathies, potentially reflecting underlying genetic interactions⁶⁵. A case report additionally described sudden infant death associated with dilated cardiomyopathy and PKD1/junctophilin gene variants⁶⁶. Despite these multiple lines of evidence, mechanisms whereby PC1 regulates cardiac development remain poorly understood, and their elucidation is essential for advancing our understanding of both heart formation and adult cardiac pathology in ADPKD.

4. Mechanotransduction

Mechanotransduction encompasses several structural models, including the bilayer tension model, the tethered protein model, and the protein unfolding model. Although direct mechanical activation of polycystins has not been demonstrated, PC1 associates with major mechanosensitive complexes — including focal adhesions and filamentous networks — and is required for renal flow sensing, positioning it as an integrative hub that translates physical stimuli into Ca²⁺ homeostasis and transcriptional responses.

Single-molecule force spectroscopy and atomic force microscopy studies have consistently demonstrated high elasticity of the PC1 extracellular region, attributed to extensible Ig-like domains that undergo sequential unfolding and refolding under mechanical stretch^67,68. Pathogenic missense mutations within the PKD domains impair this mechanical stability, implicating abnormal mechanosensing in disease⁶⁹. The REJ module — located between the GPS site and TM1 — additionally contains FNIII domains of varying mechanical stability, further supporting the configuration of PC1 as a mechanosensor⁴¹.

PC1 mechanosensory function is further supported by its physical interactions with extracellular matrix components and cytoskeletal proteins^70,71. PC1 co-localizes with E-cadherin and α-, β-, and γ-catenins⁷², with β-catenin specifically associating with the CTT⁷³, and its cytoplasmic tail interacting with intermediate filament proteins including vimentin, cytokeratins K8 and K18, and desmin⁷⁴. Additionally, annexin A5 — a Ca²⁺- and phospholipid-binding protein — interacts with the PC1 LRR domain⁷⁵, and multiple NTF motifs mediate interactions with collagen types I, II, and IV^76–78, suggesting that CTL–LRR associations with extracellular matrix proteins contribute to mechanotransduction signaling at cell–matrix interfaces.

A recurring limitation is the difficulty in attributing cardiovascular phenotypes exclusively to PC1-dependent mechanotransduction. PC1’s large size, low endogenous expression, susceptibility to non-specific antibody detection, and extensive proteolytic processing have historically complicated its functional characterization in vivo. Furthermore, shear stress, cyclic stretch, and extracellular stiffness act simultaneously in intact cardiovascular tissues, making it difficult to isolate the contribution of a single mechanosensory molecule to a given pathway. Many of the mechanisms described were identified in reductionist in vitro or cell-type-specific knockout models, and their relative contribution under integrated in vivo conditions remains incompletely understood. Addressing these limitations will require inducible, tissue-specific models combined with real-time mechanosensing reporters to establish the mechanotransduction-dependent versus -independent roles of PC1 in cardiovascular physiology and disease.

4.1. Mechanotransduction in Cardiovascular Tissues

In endothelial cells, PC1 localizes to the primary cilium and transduces fluid shear stress into intracellular Ca²⁺ signaling and nitric oxide (NO) production^35,79. Endothelial-specific Pkd1 deletion impairs flow-mediated hyperpolarization and vasodilation and elevates arterial blood pressure, establishing PC1 as necessary for vascular tone control⁸⁰. In VSMCs, PC2 tonically inhibits stretch-activated cation channels (SACs), and PC1 reverses this inhibition, such that the PC1/PC2 ratio regulates SAC activity and myogenic responses to intraluminal pressure⁸¹. Together, these findings position PC1 as a central regulator of vascular mechanotransduction, integrating shear- and stretch-dependent cues to coordinate endothelial function and smooth muscle activity.

In cardiomyocytes, PC1 mediates cellular adaptations to mechanical load more than shear stress, with several studies demonstrating its role in hypertrophic signaling pathways^82–84. Its function in the setting of mechanical unloading, however, remains poorly understood. Collectively, PC1 emerges as an evolutionarily conserved mechanosensor that, across the vasculature and heart, integrates shear, stretch, and matrix stiffness cues to regulate Ca²⁺ signaling, gene expression, and tissue remodeling; its dysfunction impairs mechanical homeostasis and predisposes to structural and functional pathology.

4.2. Polycystins and Mechanotransduction in Other Tissues

4.2.1. Kidney:

The PC1/PC2 complex localizes to primary cilia and the plasma membrane of renal tubular epithelial cells, where urine flow-induced ciliary deflection is detected by the PC1 extracellular domain and transduced into a biochemical signal^85–88. This triggers PC2 activation and Ca²⁺ influx into the cilium and cytoplasm, subsequently releasing Ca²⁺ from intracellular stores^89,90 — a mechanism central to PC1-dependent Ca²⁺ signaling in the kidney.

4.2.2. Bone:

PC1 is highly expressed in osteoblasts, osteocytes, periosteal stem/progenitor cells (PSPCs), and osteoclast precursors²⁰. Conditional Pkd1 deletion in osteocytes reduces bone mineral density, impairs trabecular and cortical architecture, and blunts the anabolic response to mechanical loading⁹¹, establishing PC1 as essential for osteocytic mechanotransduction. Mechanistically, PC1 CTT cleavage and nuclear translocation enhances TAZ transcriptional activity^92,93, promoting Runx2 expression and osteoblast differentiation⁹². When exposed to cyclic stretch, PC1 additionally regulates the calcineurin–NFAT pathway, with PC1 inhibition preventing NFATc1 nuclear translocation and suppressing Runx2 expression^94,95. In PSPCs, PC1-dependent TAZ activation drives osteochondral differentiation, and its deletion delays fracture healing in vivo⁹⁵, indicating a broader role for PC1 in skeletal regeneration.

5. Cardiovascular Manifestations in ADPKD

Cardiovascular complications represent the leading cause of morbidity and mortality in ADPKD. Here, we review the molecular pathways and clinical manifestations underlying these complications, focusing primarily on PC1. As most available clinical data do not allow clear discrimination between PKD1- and PKD2-associated features, and as PKD1 variants account for the vast majority of ADPKD cases, general ADPKD findings are considered broadly applicable to PKD1 deficiency; PKD1-specific phenotypes are indicated where data permit. Throughout, it remains challenging to distinguish primary cardiovascular effects of PC1/PC2 deficiency from secondary consequences of impaired renal function. A summary of these findings and outstanding questions is presented in Figure 3. The cardiovascular manifestations associated with specific PKD1 and PKD2 mutation types are summarized in Table 1.

Figure 3.

Cardiovascular Manifestations of Polycystin-1 (PC1) and Polycystin-2 (PC2) Dysfunction in ADPKD. IDCM: idiopathic dilated cardiomyopathy; MVP: mitral valve prolapse; ICAs: intracranial aneurysms; TAA: thoracic aortic aneurysm; CAD: coronary artery disease; FGF23: Fibroblast Growth Factor 23.

Table 1. PKD1 and PKD2 Mutation Types and Associated Cardiovascular Manifestations in ADPKD.

CV, cardiovascular; ICA, intracranial aneurysm; LVH, left ventricular hypertrophy; MVP, mitral valve prolapse; QTc, corrected QT interval.

Mutation / Variant Type	Gene	CV Manifestation / Phenotype	References
Truncating mutations (nonsense, frameshift, splicing)	PKD1	ICA; earlier rupture	96,97
		LVH	98,99
Non-truncating mutations (missense)	PKD1/PKD2	Systemic hypertension	100,101
Large genomic deletions / rearrangements	PKD1	MVP; aortic root dilatation	102,103
Hypomorphic / mild missense variants	PKD2	Systemic hypertension; milder CV course	104,105
Any pathogenic variant	PKD1 / PKD2	ICA — both genes	106,107
Somatic / de novo mutations	PKD1	Aortic aneurysm & dissection (rare)	108–110
Germline pathogenic variant (general)	PKD1 / PKD2	Arrhythmia / prolonged QTc	111
Truncating mutations (nonsense)	PKD1/PKD2	Dilated Cardiomyopathy	65,66

5.1. Hypertension

Polycystins regulate different signaling pathways in renal epithelial cells, contributing to the maintenance of their function and homeostasis. PC1/PC2 mutations reduce Ca²⁺ entry through PC2 and Ca²⁺ release from the ER^33,112,113, lowering cytoplasmic Ca²⁺ and driving cAMP accumulation, which promotes cell proliferation via MAPK/ERK^113,114. PC1 additionally exerts tonic inhibition of mTORC1 through TSC1/TSC2, such that its loss activates this complex and drives further proliferation^115,116. These pathways, together with nuclear regulators (p21), GPCR signaling, and AKT, converge to promote renal cyst development^113,117,118. The CTT has also been shown to interact with the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT), suppressing cystic disease in an NNT-dependent manner¹¹⁹.

Progressive cyst enlargement compresses adjacent renal vasculature, generating focal ischemia that activates the intrarenal renin-angiotensin-aldosterone system (RAAS) — evidenced by increased renin and AT1 receptor expression in cyst-lining epithelial cells and elevated urinary angiotensinogen in animal models and patients — as well as the sympathetic nervous system and local endothelin-1 (ET-1) production^120–123. This intrarenal RAAS activation precedes and is independent of GFR (glomerular filtration rate) decline, explaining the early onset of hypertension in ADPKD^120,124,125. Hypertension affects ~30% of PKD1 and ~11% of PKD2 patients by age 40¹⁰¹, with incidence reaching 75% for PKD1 truncating and 70% for PKD1 non-truncating variants (mean age of diagnosis 33–36 years)¹²⁶. The higher hypertension frequency among patients with a family history suggests additional, yet unidentified, genetic susceptibility factors¹²⁷.

5.2. Cardiac Hypertrophy and Cardiomyopathies

Left ventricular hypertrophy (LVH) is a common extra-renal manifestation of ADPKD and a major contributor to heart failure (HF), arrhythmias, and cardiovascular mortality¹²⁸. Clinical evidence directly implicates intrarenal RAAS activation in the development of LVH and diastolic dysfunction, as demonstrated by the strong association between RAAS activation and increased left ventricular mass index, and by the sustained regression of LVH achieved with long-term angiotensin-converting enzyme (ACE) inhibition^122,129,130. Concurrently, cyst-lining epithelial cells ectopically produce FGF23, whose serum levels are disproportionately elevated relative to the degree of renal insufficiency^131,132, accompanied by a reduction in soluble Klotho that correlates with kidney volume rather than GFR¹³³. Although direct cardiac evidence in ADPKD is lacking, FGF23/Klotho imbalance is an established driver of LVH via FGFR4/PLCγ/calcineurin/NFAT signaling in other chronic kidney disease (CKD) settings¹³⁴, suggesting a similar contribution in this disease. Collectively, renal-derived angiotensin II and FGF23 emerge as primary mediators of cardiac hypertrophy in ADPKD.

Analysis of Mayo Clinic medical records identified a likely association between ADPKD and cardiomyopathies, suggesting that PKD1 and PKD2 pathogenic variants may predispose to primary cardiomyopathies⁶⁵, including idiopathic dilated and hypertrophic obstructive forms⁶⁵. The precise mechanisms whereby renal-derived factors contribute to their development remain to be established; however, RAAS-driven hypertension may contribute to progression toward HF⁶. In Pkd1-deficient mouse models, galectin-3 has been proposed as a mediator of cardiac fibrosis and dysfunction in ADPKD¹³⁵, though whether circulating galectin-3 of renal origin similarly contributes to cardiac remodeling in ADPKD remains to be ascertained.

5.3. Vascular Abnormalities

ADPKD is associated with several vascular abnormalities, including aneurysms and arterial dissections, primarily involving intracranial arteries and the aorta¹¹⁰; cases of cervicocephalic, vertebral, and coronary arteries involvement have also been reported¹³⁶.

Mechanical compression of peritubular vasculature by expanding cysts creates focal ischemic niches throughout the renal parenchyma. This focal ischemia induces HIF-1α accumulation in cyst-lining epithelial cells, driving upregulation of endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) — both detectable at elevated concentrations in the urine of ADPKD patients and correlating with total kidney volume and rate of renal function decline^137–139. Whether these cyst-derived mediators reach the systemic circulation in biologically relevant concentrations and directly contribute to vascular endothelial dysfunction beyond the kidney remains to be formally demonstrated. Chronically elevated angiotensin II, derived from intrarenal RAAS activation¹²³, may induce VSMC proliferation and migration through AT1 receptor signaling — a mechanism well-established in non-ADPKD vascular models¹⁴⁰ — potentially contributing to accelerated vascular remodeling in ADPKD, though direct evidence in ADPKD vascular tissue remains limited.

A key molecular mechanism linking cyst-derived ischemic signals to systemic endothelial dysfunction is the accumulation of asymmetric dimethylarginine (ADMA) — an endogenous eNOS inhibitor whose levels are elevated in ADPKD patients with fully preserved renal function; the precise mechanism whereby cyst expansion drives ADMA accumulation remains incompletely understood, though increased oxidative stress and reduced renal clearance have been proposed¹⁴¹. In experimental PKD models, renal NOX4 upregulation in tubular epithelial and endothelial cells generates reactive oxygen species that reduce eNOS expression, impair NO bioavailability, and promote peritubular capillary loss from as early as 4 weeks of age, preceding measurable renal functional decline¹⁴². Together, these signals converge to impair endothelium-dependent vasodilation, a process detectable in normotensive ADPKD patients before the onset of hypertension or renal insufficiency¹⁴³. Consistent with this early vascular injury, increased vascular inflammation, carotid intima-media thickness, and elevated pulse wave velocity are present in both normotensive and hypertensive ADPKD patients with preserved renal function; notably, ascorbic acid infusion improves flow-mediated dilation specifically in ADPKD patients, directly implicating oxidative stress as a mediator of endothelial dysfunction¹⁴⁴.

At the structural level, ADPKD patients manifest an ~5.5-fold elevated risk of aortic aneurysm and dissection, with hypertension as the strongest modifying risk factor¹⁰⁸. The Pkd1^nl/nl hypomorphic mouse model — which reproduces ADPKD through reduced Pkd1 expression and progressive renal cyst development — develops spontaneous aortic dissections associated with disruption of vascular wall structural integrity¹⁰⁹, suggesting that PC1 deficiency directly compromises aortic wall integrity beyond the hemodynamic effects of renal-driven hypertension, though the relative contribution of each mechanism in ADPKD patients remains to be formally established.

6. Polycystin-1 as a Primary Regulator of Cardiovascular Function and Pathological Remodeling

Whereas the cardiovascular manifestations of ADPKD — including hypertension, vascular aneurysms, andf LVH — are commonly attributed to secondary effects of chronic kidney disease and systemic hypertension, mounting evidence supports a cell-autonomous role for PC1 in the heart. PC1 acts as a primary mechanosensor in cardiomyocytes, translating mechanical stress and metabolic demands into intracellular biochemical signals independent of renal influence. Notably, this function appears to be PC2-independent, as cardiomyocyte-specific PC2 knockout mice exhibit no baseline cardiac phenotype, whereas PC1 knockout mice develop cardiac dysfunction and HF^84,145. Despite these advances, the signaling pathways governed by PC1 in cardiomyocytes remain incompletely elucidated. The following sections review the cell-autonomous roles of PC1 in cardiac function and vascular remodeling, highlighting key knowledge gaps. Figure 4 summarizes the cell-autonomous signaling mechanisms regulated by PC1 in the cardiovascular system. The experimental models used to investigate the cell-autonomous cardiovascular roles of PC1, organized by cell type, are summarized in Table 2.

Figure 4.

Cell-autonomous signaling mechanisms regulated by PC1 in the cardiovascular system. (A) PC1-dependent signaling pathways in cardiomyocytes under baseline conditions, mechanical stretch, humoral signaling (IGF-1), and ischemia/reperfusion. (B) Cell-autonomous roles of PC1 in vascular smooth muscle cells and endothelial cells in response to intraluminal pressure and shear stress, respectively. (a), activated form; AKT, protein kinase B; APD, action potential duration; BIN1, bridging integrator 1; LTCC, L-type calcium channel subunit (Cav1.2, Cavβ2); CTGF, connective tissue growth factor; CTT, C-terminal tail; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated kinase 1/2; FoxO1, forkhead box protein O1; GPS, G protein-coupled receptor proteolytic site; IGF-1, insulin-like growth factor 1; IGF-1R, IGF-1 receptor; Kv, voltage-gated potassium channel; MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin; NFAT, nuclear factor of activated T cells; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PC1, polycystin-1; PC2, polycystin-2; PKC, protein kinase C; PTP1B, protein tyrosine phosphatase 1B; SAC, stretch-activated channel; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SMAD3, mothers against decapentaplegic homolog 3; TGFβ-1, transforming growth factor beta-1; VSMC, vascular smooth muscle cell.

Table 2. Experimental Models Used to Study Cell-Autonomous PC1 Function in the Cardiovascular System.

Summary of experimental models used to investigate the cell-autonomous cardiovascular roles of PC1. Models with concurrent renal phenotype are included where the cardiovascular findings are directly attributable to PC1 loss. APD, action potential duration; ARCFs, adult rat cardiac fibroblasts; AKT, protein kinase B; LTCC, L-type calcium channel subunit (Cav1.2, Cavβ2); CM, cardiomyocyte; CTT, C-terminal tail; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated kinase 1/2; FAO, fatty acid oxidation; FoxO1, forkhead box protein O1; FSP1, fibroblast-specific protein 1; GPS, G protein-coupled receptor proteolytic site; hESC, human embryonic stem cell; hiPSC, human induced pluripotent stem cell; IK/SK, intermediate/small conductance Ca²⁺-activated K+ channels; KO, knockout; MEK, mitogen-activated protein kinase kinase; MI, myocardial infarction; mTOR, mechanistic target of rapamycin; NMVMs, neonatal mouse ventricular myocytes; NO, nitric oxide; NRCFs, neonatal rat cardiac fibroblasts; NRVMs, neonatal rat ventricular myocytes; OXPHOS, oxidative phosphorylation; PC1, polycystin-1; PC2, polycystin-2; SAC, stretch-activated channel; SMAD3, mothers against decapentaplegic homolog 3; TAC, transverse aortic constriction; TAD, thoracic aortic dissection; TGFβ-1, transforming growth factor beta-1; VSMC, vascular smooth muscle cell.

Model Type	Genetic Model	Experimental Approach	Key Findings	References
Cardiomyocytes
Mouse	Pkd1del17–21βgeo (+/− and −/−)	Germline knockout (gene targeting)	Heterozygous: adult mice develop renal and hepatic cysts (late onset). Homozygous: embryonic lethality (E13.5–14.5); primary cardiovascular defect	63
Mouse / Primary cells	CM-specific Pkd1 KO / PC1 knockdown (siRNA) in NRVMs	Conditional knockout (Cre-lox) + siRNA knockdown	Required for TAC-induced compensatory hypertrophy; CTT sufficient to trigger hypertrophy; Cav1.2 stability reduced upon knockdown	84
Primary cells	NRVMs (siRNA knockdown) / PC1-CTT overexpression	siRNA-mediated PC1 knockdown + adenoviral overexpression	Gβγ–AKT–Cavβ2 pathway and CTT G protein-binding domain required for LTCC stabilization and Cav1.2 stability under mechanical stretch	83
Mouse / Primary cells / Cell line	CM-specific Pkd1 KO / adult cardiomyocytes · hESC-derived cardiomyocytes · HEK293	Conditional knockout (Cre-lox) + heterologous overexpression	CTT suppresses Kv4.3, Kv1.5, and Kv2.1; KO shortens APD and impairs contractility; R4228X mutation abolishes Kv suppression	146
Mouse / Primary cells	Pkd1 heterozygous mice / NRVMs (rat) · hiPSC-derived cardiomyocytes	Heterozygous mouse + siRNA knockdown	Knockdown promotes mitochondrial fission and mitophagy via AKT/FoxO1 dysregulation; reduced OXPHOS subunit levels; replicated in rat and human cardiomyocytes	147
Mouse / Primary cells	Pkd1V/V (homozygous knockin) / NMVMs (Pkd1V/V, P1–P3)	Non-cleavable GPS knockin (T3041V substitution)	GPS cleavage required for FAO and mitochondrial integrity; cardiac dysfunction without hypertrophy; cell-autonomous effect confirmed in Pkd1V/V NMVMs	148
Cardiac Fibroblasts
Mouse / Primary cells	Fibroblast-specific Pkd1 KO (FSP1-Cre; Pkd1fl/fl) / NRCFs and ARCFs (siRNA)	Conditional fibroblast-specific KO (FSP1-Cre) + siRNA knockdown in primary cells	Ciliary PC1 mediates TGFβ-1–SMAD3 fibrogenesis; PC1 loss impairs post-MI fibrotic remodeling	28
Vascular Smooth Muscle Cells
Mouse / Ex vivo	VSMC-specific Pkd1 KO (Pkd1SMdel/del) / isolated mesenteric artery myocytes	Conditional knockout (Cre-lox)	PC1/PC2 ratio governs SAC activity and myogenic tone; PC2 tonically inhibits SACs, reversed by PC1; LTCC activity unaffected	81
Mouse	Pkd1nl/nl	Hypomorphic knockin (reduced Pkd1 expression ~26% of normal)	Dissecting aortic aneurysms; medial degeneration; VSMC switch toward synthetic phenotype; required for vessel wall structural integrity	109
Human tissue / Primary cells	TAD patient aortic tissue / human aortic VSMCs (siRNA + CTT overexpression)	siRNA-mediated PC1 knockdown + PC1-CTT overexpression in human aortic VSMCs	Loss activates MEK/ERK/c-Myc promoting synthetic phenotype; CTT overexpression suppresses ERK phosphorylation; Ser4166 functionally required	149
Human tissue / Primary cells	TAD patient aortic tissue / human aortic VSMCs (shRNA knockdown)	shRNA-mediated PC1 knockdown in primary human aortic VSMCs	Loss promotes synthetic phenotype via mTOR/S6K/S6; contractile markers and collagen deposition altered; reversed by rapamycin	150
Endothelial Cells
Primary cells	Pkd1null/null aortic endothelial cells / Tg737orpk/orpk endothelial cells	Genetic loss-of-function in primary endothelial cells + laminar flow assay	Ciliary PC1 required for shear stress–induced Ca2+ signaling and NO production; fluid shear sensing is cilia-specific	35
Mouse / Ex vivo	Pkd1 ecKO (Cdh5-CreERT2; Pkd1fl/fl)	Conditional EC-specific knockout (Cdh5-CreERT2, tamoxifen-inducible)	KO impairs flow-mediated vasodilation via eNOS and IK/SK; hypertension without renal changes	79
Mouse / Ex vivo	Cdh5-CreERT2; Pkd1fl/fl	Conditional EC-specific knockout (Cdh5-CreERT2, tamoxifen-inducible)	KO impairs flow-mediated dilation and acetylcholine-induced relaxation; hypertension without renal cysts; arteriovenous fistula maturation impaired	80

6.1. Hypertrophy, Heart Failure, and Cardiac Contractility

The transition from compensated cardiac hypertrophy to HF is driven by chronic stress and maladaptive signaling, with PC1 emerging as a critical cell-autonomous component of the cardiomyocyte stress response machinery.

The role of PC1 as a cardiomyocyte mechanosensor was first described in 2015, when cardiomyocyte-specific PC1 knockout mice subjected to transverse aortic constriction (TAC)-induced pressure overload failed to develop compensatory hypertrophy, instead progressing directly to HF⁸⁴. In the same study, PC1 deficiency was associated with reduced Cav1.2 protein levels and decreased RCAN1.4 expression — a transcriptional reporter of calcineurin/NFAT pathway activity — and the CTT of PC1 was identified as sufficient to drive Ca²⁺-calcineurin/NFAT-mediated hypertrophy in cardiomyocytes subjected to both static and cyclic mechanical stress in vitro, although the mechanism whereby PC1 regulates L-type calcium channel (LTCC) content in cardiomyocytes was not investigated in that study⁸⁴.

Subsequent work in neonatal rat ventricular cardiomyocytes further delineated the mechanism whereby PC1 maintains Cav1.2 protein stability in the setting of mechanical stress. Specifically, the Gβγ-binding domain within the CTT of PC1 — coupled to a Gi/o heterodimeric protein — was identified as responsible for AKT activation, which in turn phosphorylates the auxiliary subunit Cavβ2, ultimately stabilizing the Cav1.2 pore-forming subunit at the plasma membrane⁸³. These findings highlight the CTT of PC1 as a critical structural determinant linking mechanical stimuli to the transcriptional regulation of the hypertrophic gene program.

PC1 regulates cardiac function through at least two complementary mechanisms. On the one hand, PC1 regulates LTCC protein content, as described above. On the other hand, cardiomyocyte-specific PC1 knockout models exhibit impaired systolic and diastolic function alongside shortened action potential duration (APD), attributable to increased outward K⁺ currents through multiple voltage-gated potassium channels, including Kv4.3, Kv1.5, and Kv2.1. This shortened APD reduces sarcoplasmic reticulum Ca²⁺ stores and impairs Ca²⁺ transients, thereby compromising contractility. Mechanistically, the CTT of PC1 directly inhibits Kv4.3 via physical interaction, and the disease-associated human mutant PC1^R4228X loses this suppressive effect, directly linking PC1 loss-of-function to dysregulated membrane repolarization¹⁴⁶.

In addition to its electrophysiological functions, PC1 plays a fundamental role in maintaining cardiomyocyte structural organization. BIN1 is a protein crucial for tubulogenesis and maintenance of cardiac T-tubule ultrastructure^151–153, anchoring key excitation-contraction coupling components including Cav1.2 and RyR2. Cardiomyocyte-specific PC1 knockout mice exhibit progressive reduction in BIN1 expression — particularly cardiac isoforms — accompanied by T-tubule disorganization and dilated cardiomyopathy¹⁵⁴, establishing PC1 as a regulator of T-tubule integrity and contractile function. The signaling pathway linking PC1 to BIN1 expression remains unknown, and whether this axis intersects with PC1-dependent LTCC stabilization has not been investigated, suggesting distinct and potentially complementary intracellular mechanisms.

Nevertheless, the YAP/TAZ axis represents a plausible downstream mediator given its established role in mechanical stress responses and cardiovascular disease pathogenesis^155–157. Supporting this hypothesis, TAZ is regulated by PC1 in bone tissue^92,93, YAP/TAZ governs c-Myc expression in both ADPKD and VSMCs^158–161, and c-Myc overexpression represses BIN1 in cancer cells¹⁶², collectively suggesting a PC1–YAP/TAZ–c-Myc–BIN1 regulatory axis in cardiomyocytes that warrants future investigation.

Beyond Ca²⁺ handling, PC1 engages with key survival and hypertrophic pathways. In neonatal rat cardiomyocytes in vitro, PC1 is required for insulin-like growth factor 1 (IGF-1)-induced hypertrophy⁸², and its deficiency impairs IGF-1 receptor autophosphorylation and downstream AKT and ERK1/2 activation through de-repression of PTP1B — an effect absent in phenylephrine-induced hypertrophy, indicating stimulus specificity. Collectively, these findings underscore the complexity of PC1 function in cardiomyocytes, acting as both a mechanosensor and a regulator of humoral signals, potentially through the assembly of a multiprotein complex integrating multiple upstream inputs.

6.2. Cardiac Metabolism

Cardiomyocytes produce and consume approximately 6 kg of ATP daily, and the failing heart characteristically undergoes a metabolic shift from fatty acid oxidation toward inefficient glucose utilization with consequent ATP reduction.

PC1 regulates cardiac mitochondrial metabolism through at least two distinct mechanisms. First, a C-terminal cleavage product of PC1 translocates to the mitochondrial matrix where it is required for mitochondrial morphology maintenance and fatty acid oxidation, as demonstrated in renal epithelial cells in vitro and in Drosophila in vivo⁵⁶. Extending these findings to the heart, Pkd1^V/V knockin mice — expressing a non-cleavable PC1 at the GPS site — exhibited cardiac dysfunction without hypertrophy, reduced fatty acid oxidation evidenced by decreased p-AMPK, p-ACCβ, CPT1B, and PPARα levels, increased glucose utilization, and a higher proportion of smaller mitochondria accompanied by increased apoptosis and inflammation. These metabolic and structural alterations were replicated in Pkd1^V/V neonatal cardiomyocytes in vitro¹⁴⁸, establishing a cell-autonomous role of PC1 cleavage in cardiac metabolic regulation.

Second, PC1 knockdown in cardiomyocytes in vitro reduces OXPHOS complex subunit protein levels, mitochondrial membrane potential, oxygen consumption, and ATP production¹⁴⁷. These alterations are associated with deregulation of the AKT/FoxO1 axis, whereby loss of PC1-dependent AKT activation leads to FoxO1 nuclear translocation and transcriptional dysregulation of mitochondrial morphology and quality control genes, promoting mitochondrial fission and mitophagy¹⁴⁷. Whether this AKT/FoxO1 dysregulation is triggered by mechanical stimuli or operates independently of mechanosensing remains unknown.

Collectively, PC1 supports cardiac metabolic homeostasis through regulation of mitochondrial structure and oxidative capacity. As mitochondrial dysfunction sensitizes cardiomyocytes to ischemic damage, these findings provide a mechanistic basis linking PC1 deficiency to increased vulnerability to ischemia/reperfusion (I/R) injury, as discussed below.

6.3. Ischemia/Reperfusion Injury

Although reports on PC1’s role in cardiac I/R injury remain scarce, converging evidence suggests a cardioprotective function operating through distinct cell-type-specific mechanisms.

Infarct size during myocardial infarction is larger in cardiomyocyte-specific PC1 knockout mice and is associated with impaired pro-survival AKT activation. In parallel, in vitro evidence demonstrates that PC1 regulates paracrine release of connective tissue growth factor (CTGF) from cardiomyocytes in a PC1/AKT-dependent manner, governing cardiac fibroblast differentiation into myofibroblasts and linking cardiomyocyte PC1 signaling to post-ischemic fibrotic remodeling¹⁶³.

In cardiac fibroblasts, PC1 localizes to primary cilia, where it is required for TGFβ-1-induced fibrogenesis through SMAD3 phosphorylation, extracellular matrix protein production, and fibroblast contractility. Fibroblast-specific PC1 knockout mice exhibit exacerbated pathological remodeling following myocardial infarction in vivo, and in vitro depletion of primary cilia and PC1 attenuates TGFβ-1-dependent pathway activation²⁸, collectively establishing ciliary PC1 as a required component of the TGFβ-1/SMAD3 fibrogenesis axis. Although not directly investigated, the ciliary localization of PC1 raises the possibility that this fibrogenic response is mechanosensitive, potentially triggered by the increased myocardial stiffness and stretch accompanying post-ischemic remodeling.

At the mitochondrial level, although not directly studied in the context of I/R, PC1 deficiency promotes mitochondrial fission, reduces functional mitochondrial mass, and activates mitophagy through the AKT/FoxO1 axis under basal conditions in vitro¹⁴⁷. Together with the impaired fatty acid oxidation and reduced OXPHOS capacity described above, these pre-existing mitochondrial alterations suggest that PC1 plays a protective role during I/R through maintenance of mitochondrial quality control and metabolic homeostasis, rendering PC1-deficient cardiomyocytes intrinsically vulnerable to ischemic damage — a hypothesis that warrants direct investigation.

6.4. Vascular Diseases

As previously discussed, ADPKD is associated with a broad spectrum of vascular complications¹⁶⁴. PC1 plays fundamental cell-autonomous roles in the vasculature, influencing vessel integrity, endothelial function, mechanosensation, and susceptibility to aneurysm and dissection^150,165. Clinical observations — including early hypertension, increased arterial stiffness, intracranial aneurysm prevalence, and aortic pathologies — suggest a vascular phenotype stemming directly from PC1 deficiency¹⁶⁴. Both VSMCs and endothelial cells express PC1, and dysfunction in either compartment compromises arterial wall architecture and function.

6.4.1. PC1 Signaling in VSMCs:

PC1 fulfills both structural and mechanosensory roles in VSMCs. At the structural level, homozygous Pkd1 mutant mice (Pkd1L) develop dissecting aortic aneurysms and medial degeneration in vivo, establishing PC1 as essential for arterial wall tensile integrity¹⁶⁵. In contrast, VSMC-specific Pkd1 knockout mice develop normally but exhibit reduced arterial myogenic tone in vivo, demonstrating a regulatory rather than solely structural role⁸¹.

The intraluminal pressure environment to which VSMCs are continuously exposed requires refined mechanosensory machinery. PC1 and PC2 form a dosage-dependent complex that regulates stretch-activated cation channels (SACs) in response to intraluminal pressure — a stimulus distinct from the shear stress sensed by endothelial polycystins. PC2 tonically inhibits SAC activity, and PC1 reverses this inhibition; the net PC1/PC2 ratio thus determines SAC opening, downstream Ca²⁺ influx, and myogenic vasoconstriction through interaction of PC2 with filamin A, an actin crosslinking protein critical for SAC regulation. VSMC-specific PC1 deletion in vivo reduces SAC activity and impairs myogenic tone, while PC2 depletion in PC1-deficient arteries rescues both⁸¹. Notably, LTCC activity was unaffected by PC1 inactivation, indicating specificity of the PC1/PC2 complex for SAC-mediated pressure sensing.

Beyond mechanosensing, PC1 suppresses pathological VSMC phenotypic switching. In vitro PC1 silencing triggers a shift toward the synthetic phenotype — characterized by reduced contractile markers (SM22α, α-SMA, calponin), increased proliferation and migration, and cytoskeletal disorganization — driven by mTOR/S6K/S6 hyperactivation, reversible by rapamycin treatment¹⁵⁰. In a complementary in vitro study using human aortic VSMCs, PC1 downregulation activated the MEK/ERK/c-Myc axis, promoting proliferation and phenotypic switching; CTT overexpression suppressed ERK phosphorylation and reversed these changes, and mutation of Ser⁴¹⁶⁶ within the CTT abolished this regulatory effect, identifying this residue as functionally required¹⁴⁹.

Collectively, PC1 functions in VSMCs as a pressure-sensing mechanotransducer via the PC1/PC2–SAC–filamin A axis, and as a suppressor of pathological remodeling through inhibition of mTOR/S6K and MEK/ERK/c-Myc signaling.

6.4.2. Endothelial PC1:

Beyond its role in VSMCs, PC1 plays critical mechanosensory and structural functions in the endothelium through compartment-specific mechanisms in response to shear stress. In the primary cilium, PC1 and PC2 form a mechanosensory complex that transduces fluid shear stress into intracellular Ca²⁺ signals and NO production, as demonstrated in vitro in Pkd1^null/null aortic endothelial cells subjected to laminar flow³⁵. The downstream cascade linking ciliary Ca²⁺ entry to NO synthesis involves sequential activation of calmodulin, PKC, and Akt/PKB, ultimately phosphorylating eNOS — a mechanism attributed to PC2 as the Ca²⁺-conducting subunit of the ciliary complex, demonstrated in vitro in endothelial cells from Pkd2 knockout mice and ADPKD patients subjected to laminar shear stress and confirmed ex vivo in isolated arteries³⁴ — suggesting that PC1 and PC2 may act cooperatively to couple shear stress detection to NO production.

PC1’s mechanosensory function extends beyond the cilium: at the plasma membrane, the PC1/PC2 complex activates Ca²⁺-dependent cation currents in response to shear stress, engaging eNOS and Ca²⁺-activated K⁺ channels (IK/SK), and producing arterial hyperpolarization and flow-mediated vasodilation⁷⁹. Endothelial cell-specific Pkd1 knockout mice exhibit impaired flow-mediated dilation and elevated systemic blood pressure without renal structural changes, confirming a direct vascular role of endothelial PC1 independent of renal disease⁷⁹. A second independent endothelial-specific Pkd1 deletion model in vivo similarly demonstrates impaired flow-mediated dilation and loss of acetylcholine-induced relaxation⁸⁰. Additionally, primary cilia deficiency in endothelial cells — studied using the ciliary assembly-deficient Tg737^orpk/orpk model rather than PC1-specific deletion — reduces expression and disrupts organization of junction proteins including ZO-1, ZO-2, and claudins, increasing endothelial permeability under low wall shear stress in vitro, though whether this effect is specifically attributable to PC1 remains to be established¹⁶⁶.

The vascular mechanisms described above converge to explain the early onset of hypertension in ADPKD, which frequently precedes cyst expansion and cannot be fully accounted for by renal RAAS activation alone. PC1 deficiency simultaneously impairs shear stress-dependent NO production in endothelial cells^87,140, reduces myogenic tone through dysregulation of the PC1/PC2–SAC–filamin A axis¹⁴², and compromises intrarenal RAAS suppression. That endothelial- and VSMC-specific PC1 deletion each independently recapitulate the hypertensive phenotype without renal cystic disease^140,141, fundamentally reframes ADPKD-associated hypertension as a primary vasculopathy, suggesting that strategies targeting endothelial NO bioavailability, PC1/PC2 complex integrity, or downstream effectors such as eNOS, IK/SK channels, or mTOR/S6K may offer complementary benefit beyond conventional antihypertensive therapy.

7. Clinical Perspectives

Polycystins are increasingly recognized as mechanosensitive regulators with broad cardiovascular relevance beyond their established role in renal physiology. Structural insights into PC1 and PC2 now provide a molecular framework to reinterpret cardiovascular phenotypes associated with ADPKD — including early-onset hypertension, vascular stiffness, LVH, and increased cardiovascular mortality — and reveal potential intersections with major cardiovascular pathways involving mechanotransduction, Ca²⁺ handling, and ciliary signaling.

Several clinical observations highlight underutilized opportunities for cardiovascular risk stratification in ADPKD. Normotensive ADPKD patients exhibit an abnormal diastolic blood pressure response during exercise¹⁶⁷, a finding also observed in unaffected normotensive relatives¹⁶⁸, suggesting a familial impairment of exercise-induced vasodilation and a heritable predisposition to hypertension independent of overt renal disease. Additionally, a high prevalence of non-dipping nocturnal hypertension has been reported in children with ADPKD¹⁶⁹, further supporting early autonomic and vascular dysregulation. Collectively, these findings identify abnormal blood pressure responses as powerful yet underutilized prognostic markers for accelerated LVH and long-term cardiovascular risk.

PC1/PC2 dysfunction impairs cardiomyocyte Ca²⁺ homeostasis, contributing to structural remodeling measurable as diastolic dysfunction and reduced coronary flow reserve — functional endpoints amenable to non-invasive assessment by advanced echocardiography or cardiac MRI. Given the established role of polycystins in regulating intracellular Ca²⁺ signaling, Ca²⁺ channel modulators warrant renewed investigation as potential therapeutic agents capable of stabilizing Ca²⁺ homeostasis in PC1/PC2-deficient cells, beyond their conventional antihypertensive role.

Translating the structural and mechanistic knowledge regarding polycystins into targeted cardiovascular therapeutics represents a compelling direction for the next decade, with implications for early detection, risk stratification, and intervention in both renal and non-renal complications of ADPKD — an unmet clinical need that remains largely overshadowed by the renal manifestations of the disease.

8. Emerging AI/ML Applications in PC1-Targeted Drug Discovery

The application of AI and machine learning (ML) to drug discovery in ADPKD is nascent but rapidly evolving, with current efforts concentrated in target identification, computational drug repurposing, and direct structural targeting of the polycystin complex¹⁷⁰. Using gene expression signature reversion applied to transcriptomic datasets from pre-cystic and cystic Pkd2 mouse models, ML-driven pipelines have efficiently prioritized FDA-approved repurposing candidates¹⁷¹. Complementarily, a phenotypic high-throughput screening platform integrating computational compound annotation with functional assays in Pkd1-null and primary human ADPKD cells identified 155 candidates with selective anti-cystic activity from ~8,000 compounds¹⁷², whereas a knowledge graph-based neural network approach independently prioritized mebendazole as a candidate subsequently validated in human ADPKD cell models and in vivo¹⁷³. Collectively, these studies establish proof-of-concept for AI/ML-driven candidate prioritization in ADPKD, while also underscoring a persistent translational gap: compounds with strong preclinical efficacy have repeatedly failed to translate to clinical benefit — a limitation that computational prioritization alone cannot overcome without improved human-relevant validation platforms.

Direct AI/ML-driven targeting of PC1 itself faces substantially greater challenges. Leveraging AlphaFold-predicted structures combined with Gaussian accelerated molecular dynamics simulations, the first structural framework for PC1-directed drug design was established by elucidating binding conformations of stalk-derived peptide agonists to the PC1 C-terminal fragment¹⁷⁴. Separately, high-throughput electrophysiological screening combined with molecular docking identified potent polycystin channel antagonists and defined a pharmacophore for the polycystin family, though no channel activators emerged despite screening a diverse chemical library — a significant gap given that ADPKD is a loss-of-function disease¹⁷⁵. The structural complexity of PC1 — a 4,303-amino acid transmembrane protein whose complete three-dimensional structure remains experimentally unresolved — combined with the inherent limitations of AI-predicted static models in capturing conformational dynamics and allosteric transitions, means that no validated small-molecule PC1 modulator has yet emerged. Progress will likely require iterative integration of cryo-EM structural data, molecular dynamics simulations, and organoid-based validation platforms¹⁷⁰.

9. Knowledge Gaps

Despite major advances in polycystin structural biology, several fundamental questions remain unanswered.

9.1. Mechanotransduction mechanisms and PC1–PC2 complex regulation in native tissues.

Although structural studies have clarified PC1 architecture, the precise mechanism whereby mechanical forces are sensed and transformed into biochemical outputs remains poorly understood, particularly in cardiomyocytes, which lack primary cilia. The relative contribution of PC1 pools at the primary cilium versus the plasma membrane, ER, or junctional domains remains unresolved. Compounding this, the physiologically relevant oligomeric assembly of PC1–PC2 complexes, their stability under flow, and their regulation by post-translational modifications are unknown — especially given that PC1 fulfills functional roles independent of PC2.

9.2. Endogenous ligands and CTT downstream signaling.

PC1 functions as a receptor whose physiological and pathological ligands remain unidentified, a critical gap for the rational development of therapeutic agonists or antagonists. Equally unresolved are the precise downstream targets of PC1-CTT cleavage and how the CTT differentially regulates key pathways — including calcineurin/NFAT, mTOR, and STAT — across cardiovascular cell types, limiting its assessment as a diagnostic or therapeutic target.

9.3. Causal links between PC1 deficiency and cardiovascular phenotypes.

Although hypertension, aneurysmal disease, and endothelial dysfunction are highly prevalent in ADPKD, the specific causal pathways connecting polycystin mutations to altered cardiovascular mechanics remain incompletely established, representing the most immediate translational gap between mechanistic discovery and clinical application.

10. Conclusions

PC1 functions as a pivotal mechanosensor linking mechanical forces to cardiac and vascular remodeling. Fully elucidating the structure-function relationships of PC1 and the PC1/PC2 complex is paramount to addressing the cardiovascular mortality associated with ADPKD — an area of unmet clinical need that warrants far greater investigative focus.

Nonstandard Abbreviations and Acronyms

ACCβ

acetyl-CoA carboxylase beta

ADMA

asymmetric dimethylarginine

ADPKD

autosomal dominant polycystic kidney disease

aGPCR

adhesion G protein–coupled receptor

APD

action potential duration

ARCFs

adult rat cardiac fibroblasts

BIN1

bridging integrator 1

CAD

coronary artery disease

CFTR

cystic fibrosis transmembrane conductance regulator

CKD

chronic kidney disease

CPT1B

carnitine palmitoyltransferase 1B

cryo-EM

cryo-electron microscopy

CTF

C-terminal fragment

CTGF

connective tissue growth factor

CTL

C-type lectin domain

CTT

C-terminal tail

EGLN3

prolyl hydroxylase domain protein 3

eNOS

endothelial nitric oxide synthase

ET-1

endothelin-1

FAO

fatty acid oxidation

FGF23

fibroblast growth factor 23

FNIII

fibronectin type III (repeat motifs)

FoxO1

forkhead box protein O1

FSP1

fibroblast-specific protein 1

GAIN

GPCR autoproteolysis inducer domain

GFR

glomerular filtration rate

GPS

G protein–coupled receptor proteolytic site

hESC

human embryonic stem cell

HF

heart failure

hiPSC

human induced pluripotent stem cell

I/R

ischemia/reperfusion (injury)

ICA

intracranial aneurysm

IDCM

idiopathic dilated cardiomyopathy

IGF-1

insulin-like growth factor 1

IK/SK

intermediate/small conductance Ca²⁺;-activated K⁺ channels

KO

knockout

LDL-A

low-density lipoprotein-like domain

LRR

leucine-rich repeats

LTCC

L-type calcium channel

LVH

left ventricular hypertrophy

MCP-1

monocyte chemoattractant protein-1

MI

myocardial infarction

ML

machine learning

MVP

mitral valve prolapse

NMVMs

neonatal mouse ventricular myocytes

NNT

nicotinamide nucleotide transhydrogenase

NO

nitric oxide

NRCFs

neonatal rat cardiac fibroblasts

NRVMs

neonatal rat ventricular myocytes

NTF

N-terminal fragment

OXPHOS

oxidative phosphorylation

PC1

polycystin-1

PC2

polycystin-2

PKD1

polycystic kidney disease 1 (gene)

PKD2

polycystic kidney disease 2 (gene)

PLAT

lipoxygenase and α-toxin domain

PPARα

peroxisome proliferator-activated receptor alpha

PSPC

periosteal stem/progenitor cell

QTc

corrected QT interval

RAAS

renin-angiotensin-aldosterone system

RCAN1.4

regulator of calcineurin 1.4

REJ

receptor for egg jelly (region)

SAC

stretch-activated cation channel

TAA

thoracic aortic aneurysm

TAC

transverse aortic constriction

TAD

thoracic aortic dissection

TAZ

transcriptional coactivator with PDZ-binding motif

TM

transmembrane (domain)

TOP

tetragonal opening for polycystins (domain)

TRP

transient receptor potential (channel family)

VEGF

vascular endothelial growth factor

VSMC

vascular smooth muscle cell

WSC

wall integrity and stress response component

YAP

yes-associated protein