Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA-B-Raf-MEK-ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD's complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD.

Keywords: ADPKD; PC1/PC2; PKD; Wnt; apoptosis; cAMP; calcium; cilia; cystogenesis; fibrosis; mTOR; mitochondria.

Figure 1

The main pathological mechanisms of Polycystic Kidney Disease (PKD). Mutations in PKD1/2 genes initiate a cascade of pathological events including abnormal epithelial cell proliferation, dysregulated apoptosis, enhanced fluid secretion, oxidative stress, and chronic inflammation. These processes collectively contribute to progressive renal cyst growth, tubular distortion, and interstitial fibrosis, ultimately impairing kidney function. cAMP: cyclic adenosine monophosphate; ERK: extracellular signal-regulated kinase; mTOR: mammalian target of rapamycin; JAK-STAT: Janus kinase and signal transducer and activator of transcription; NF-κB: Nuclear Factor kappa-enhancer of activated B-cells; ROS: reactive oxygen species; NADPH: nicotinamide adenine dinucleotide phosphate; NOX4: NADPH oxidase 4; MCP-1: monocyte chemoattractant protein-1; CCR2: C-C chemokine receptor type 2. Created with Biorender.com (accessed on 12 June 2025).

Figure 2

Schematic representation of signaling pathways associated with the primary cilium in renal epithelial cells, highlighting the role of ciliary-localized receptors and proteins in cellular signaling and proliferation. The PC1/2 complex is embedded in the ciliary membrane and plays a mechanosensory role. Key ciliary G protein-coupled receptors (GPCRs) include GPR161, which promotes Hedgehog signaling and drives cell proliferation, and V2R, which increases cAMP levels. AC3 and SSTR also regulate cAMP production. Dysregulation of these pathways can lead to increased cAMP accumulation. Dysfunctional PC1 activates the mTOR pathway, contributing to cystogenesis in Polycystic Kidney Disease. GPR161: G protein-coupled receptor 161; V2R: vasopressin receptor 2; cAMP: cyclic adenosine monophosphate, AC3: adenylyl cyclase 3; SSTR: somatostatin receptor; mTOR: mammalian target of rapamycin. The red prohibition symbol (circle with a diagonal line) denotes a dysfunctional pathway. Created with Biorender.com (accessed on 12 June 2025).

Figure 3

Intracellular signaling pathways driving renal cyst formation in Polycystic Kidney Disease (PKD). This schematic illustrates the disrupted signaling cascades resulting from mutations in Pkd1 and Pkd2 in PKD. Loss of functional PC1/PC2 reduces intracellular Ca⁺² levels, leading to activation of AC6 and inhibition of PDE, which together elevate cAMP levels. Elevated cAMP activates PKA, which subsequently stimulates B-RAF, Ras, MEK, and ERK signaling cascades, promoting gene transcription, cell proliferation, and cyst growth. The Wnt/β–catenin pathway is activated through binding of Wnt ligands to the FZD receptor, resulting in inhibition of GSK-3β and stabilization of β-catenin, which translocate to the nucleus to induce transcription of proliferation-related genes. Dysregulation of this pathway contributes to epithelial cell proliferation in cyst-lining cells. The mTOR pathway is activated downstream of PI3K/Akt signaling. Akt inhibits the TSC1/2 complex, leading to activation of Rheb-GTP and mTOR. Active mTOR promotes protein synthesis via downstream targets such as S6K1 and 4EBP1, while also inhibiting autophagy. Concurrently elevated cAMP levels activate PKA, which stimulates the apical CFTR chloride channel, promoting Cl⁻ secretion into the cyst lumen. This chloride originates from basolateral uptake via NKCC1 and is supported by the Na⁺/K⁺–ATPase pump, which maintains ionic gradients. The efflux of Cl⁻ is followed by passive Na⁺ movement, regulated in part by ENaC, and water influx through AQP2, driven by the resulting osmotic gradient. Kir channels help maintain membrane potential to support continued ion transport. Loss of functional PC1 leads to aberrant activation of the JAK/STAT3 signaling pathway in cyst-lining epithelial cells. This activation promotes transcription of genes involved in cell proliferation, survival, and inflammation, contributing to cyst growth. Mitochondrial dysfunction in PKD leads to the release of mitochondrial dsDNA into the cytosol, where it is sensed by the cyclic GMP–AMP synthase (cGAS). Activation of cGAS triggers the STING pathway, which in turn activates NF-κB signaling. This cascade promotes the expression of pro-inflammatory cytokines, contributing to chronic inflammation and fibrotic remodeling in cystic kidneys. Loss of PC1 disrupts the activation of LARG, a Rho guanine nucleotide exchange factor, leading to hyperactivation of RhoA and its downstream effector ROCK. This dysregulation suppresses the Hippo pathway, resulting in nuclear accumulation of YAP/TAZ. Activated YAP/TAZ cooperates with β-catenin to upregulate c-Myc and other proliferative genes, driving abnormal epithelial cell proliferation and cyst growth in ADPKD. In the cystic microenvironment, infiltrating macrophages secrete the cytokine TWEAK, which binds to its receptor Fn14 on tubular epithelial cells. This interaction activates downstream NF-κB and ERK signaling pathways, promoting pro-inflammatory responses, epithelial cell proliferation, and cyst expansion. Red arrows indicate dysregulated pathways, and green arrows indicate activated pathways. Ca⁺²: calcium ion; PI3K: phosphoinositide 3-kinase; Akt/PKB: protein kinase B; TSC1/2: tuberous sclerosis complex 1/2; Rheb: Ras homolog enriched in brain; mTOR: mechanistic target of rapamycin; S6K1: ribosomal protein S6 kinase beta-1; 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1; Cl⁻: chloride ion; NKCC1: Na⁺-K⁺-2Cl⁻ cotransporter 1; CFTR: cystic fibrosis transmembrane conductance regulator; Na⁺: sodium ion; K⁺: Potassium ion; ENaC: epithelial sodium channel; Kir: inward-rectifier potassium channel; Na⁺/K⁺-ATPase: sodium/potassium-transporting ATPase; AC6: adenylyl cyclase 6; PDE: phosphodiesterase; B-RAF: v-Raf murine sarcoma viral oncogene homolog B1; Ras: rat sarcoma viral oncogene homolog; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; FZD: Frizzled receptor; GSK-3β: glycogen synthase kinase 3 beta; β-Catenin: beta-catenin; IP3: inositol 1,4,5-trisphosphate; IP3R: IP3 receptor; c-Fos: cellular proto-oncogene; ELK-1: ETS-like-1 transcription factor; TCF/LEF: T-cell factor/lymphoid enhancer factor; AQP2: aquaporin-2; STING: stimulator of interferon genes; JAK: Janus kinase; STAT3: signal transducer and activator of transcription 3; LARG: leukemia-associated Rho guanine nucleotide exchange factor; ROCK: Rho-associated protein kinase; YAP/TAZ: Yes-associated protein/transcriptional coactivator; TWEAK: TNF-like weak inducer of apoptosis; Fn14: fibroblast growth factor-inducible 14 receptor; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B-cells; c-Myc: cellular Myelocytomatosis oncogene. Created with Biorender.com (accessed on 12 June 2025).

Figure 4

Schematic representation of intrinsic and extrinsic apoptotic pathways in Polycystic Kidney Disease (PKD). The extrinsic pathway is initiated by ligand binding to death receptors such as Fas or TNF receptor on the cell membrane, leading to caspase-8 activation. The intrinsic (mitochondrial) pathway is triggered by cellular stress, mitochondrial dysfunction, or DNA damage, resulting in BAX/BAK-mediated mitochondrial outer membrane permeabilization (MOMP), release of cytochrome c, and caspase-9 activation. Both pathways converge on caspase-3 activation, leading to apoptotic cell death. In PKD, dysregulated apoptosis contributes to cyst epithelial cell turnover and disease progression. BAX: Bcl-2-associated X protein; BAK: Bcl-2 antagonist/killer; BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra-large; MCL-1: myeloid cell leukemia-1; TNF-α:tumor necrosis factor-alpha; APAF-1: apoptotic protease-activating factor-1; BID: BH3-interacting domain death agonist; tBID: truncated BID; FADD: Fas-associated death domain protein. Created with Biorender.com (accessed on 12 June 2025).