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Polycystic Kidney Disease

Disease Pathophysiology Research Report

2026-01-08
Falcon MONDO:0020642 Model: Edison Scientific Literature 18 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Polycystic Kidney Disease (PKD) - MONDO ID: — - Category: Mendelian (autosomal dominant and recessive forms)

Pathophysiology description Polycystic kidney disease is a systemic ciliopathy in which inherited defects in cilia-associated proteins of renal tubular epithelia trigger cyst initiation, clonal expansion, and progressive remodeling of kidney architecture, culminating in chronic kidney disease and end-stage renal disease. In autosomal dominant PKD (ADPKD), loss-of-function mutations in PKD1 (polycystin‑1, PC1) or PKD2 (polycystin‑2, PC2) compromise primary-cilium mechanosensation and calcium flux, elevating cAMP and activating proliferative kinase networks (MAPK/ERK and PI3K–AKT–mTOR). These signals reprogram epithelial metabolism toward glycolysis, drive chloride/water secretion into cyst lumens via CFTR, and promote epithelial‑initiated fibrogenesis and interstitial inflammation that together accelerate cyst growth and nephron loss (https://doi.org/10.3390/genes15010091; https://doi.org/10.3390/ijms25137173) (satariano2024thepathophysiologyof pages 8-10, song2024reprogrammingofenergy pages 1-2). In autosomal recessive PKD (ARPKD), PKHD1 (fibrocystin, FPC) and DZIP1L mutations perturb ciliary/transition-zone function and EGFR/cAMP signaling, producing collecting-duct cysts and hepato-biliary fibrosis; DZIP1L dysfunction also impairs PC1/PC2 ciliary trafficking (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10).

Core Pathophysiology 1) Ciliary dysfunction and mechanotransduction - PC1/PC2 reside at the primary cilium; loss of either reduces intraciliary/cytosolic Ca2+ and disrupts mechanosensory control of downstream growth pathways and polarity cues. Somatic “second hits” are frequent in cyst-lining cells, consistent with a two‑hit model (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - Experimental genetic deletion identifies Aurora kinase A (AURKA) as a feed‑forward driver of cystogenesis via AKT; Aurka deletion prevented cyst formation in Pkd1- and Inpp5e‑driven mouse PKD, linking ciliary control, cell-cycle regulation, and AKT signaling (https://doi.org/10.1038/s41467-023-44410-9; published Jan 2024) (tham2024deletionofaurora pages 1-2).

2) Ca2+/cAMP axis and chloride/fluid secretion - Lowered Ca2+ disinhibits adenylyl cyclases (AC5/6), raising cAMP; PKA then activates B‑Raf–MEK–ERK and PI3K–AKT and enhances CFTR-mediated Cl− secretion that drives osmotic fluid accumulation and cyst expansion (https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2). - Compartmentalized cAMP nanodomains likely exist; a 2024 thesis highlights PDE3 as a regulator of a potentially cyst-protective cAMP pool and suggests PDE3–PC2 interactions at ER–mitochondria contacts, motivating selective modulation beyond V2R blockade (Paolocci 2024; doctoral thesis) (paolocci2024campsignallingand pages 13-17, paolocci2024campsignallingand pages 1-7).

3) Proliferative kinase signaling - cAMP/PKA cooperates with receptor and integrin inputs to activate B‑Raf–MEK–ERK and PI3K–AKT–mTORC1, which promote proliferation and growth programs central to cyst enlargement. AURKA physically interacts with and regulates AKT, completing a loop that sustains cyst growth and ciliary disassembly; pharmacologic AURKA inhibition with alisertib paradoxically stabilized AURKA protein in vivo, cautioning on target modality (https://doi.org/10.1038/s41467-023-44410-9; Jan 2024) (tham2024deletionofaurora pages 1-2).

4) Hippo–YAP/TAZ and RhoA–MRTF fibrosis coupling - Hippo pathway dysregulation in PKD permits nuclear YAP/TAZ and c‑MYC-driven transcription that amplifies proliferative and fibrotic responses (https://doi.org/10.3390/cells13110984; 5 Jun 2024) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - Loss of PC1/PC2 activates RhoA, actin remodeling, and nuclear translocation of myocardin-related transcription factors (MRTF-A/B), which reprogram the cyst epithelium into a profibrotic epithelial phenotype and paracrine-prime fibroblast-to-myofibroblast transition (https://doi.org/10.3390/cells13110984; 2024) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

5) Wnt/planar cell polarity (PCP) - Noncanonical Wnt/PCP defects disturb oriented cell division and tubule architecture, contributing to dilatation and cyst initiation in inherited cystic diseases (https://doi.org/10.3390/genes15010091; 2024) (satariano2024thepathophysiologyof pages 8-10).

6) Metabolic reprogramming and mitochondrial dysfunction - Human PKD1 cyst transcriptomics show Warburg-like shifts: increased glucose uptake and lactate production with broad suppression of FAO, TCA, and OXPHOS; predicted mTORC1/HIF‑1α/MYC activation and AMPK/PGC‑1α suppression provide a regulatory scaffold for these changes (https://doi.org/10.3390/ijms25137173; 26 Jun 2024) (song2024reprogrammingofenergy pages 1-2).

7) Inflammation/immune pathways - Cystic epithelium and interstitium exhibit immune infiltration with cytokine network activation (e.g., IL‑12/23 family; STAT3), contributing to proliferation and fibrosis; STING and TWEAK/Fn14 axes are implicated as amplifiers (review synthesis) (https://doi.org/10.3390/genes15010091; 2024) (satariano2024thepathophysiologyof pages 8-10). - Interstitial fibrosis is further supported by fibroblast–macrophage crosstalk and WNT/β‑catenin signaling in CKD, consistent with profibrotic programs in cystic kidneys (contextualized to PKD) (https://doi.org/10.3390/genes15010091; 2024) (satariano2024thepathophysiologyof pages 8-10).

8) Extracellular matrix remodeling and fibrosis - Epithelial RhoA–MRTF signaling induces ECM/matricellular genes and secreted mediators that remodel the interstitium; epithelial MRTF is necessary for priming myofibroblast differentiation in PKD models (https://doi.org/10.3390/cells13110984; 2024) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

Key Molecular Players Genes/Proteins (HGNC symbol; role) - PKD1 (PC1) and PKD2 (PC2): ciliary mechanosensory complex controlling Ca2+ homeostasis; causal in ADPKD (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - PKHD1 (FPC): ciliary membrane/transition-zone protein; causal in ARPKD; DZIP1L: ciliary trafficking; ARPKD modulator (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - CFTR: apical Cl− channel driving fluid secretion in cysts under cAMP control (https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2). - AURKA: kinase/ciliogenesis regulator forming a feed‑forward loop with AKT driving cystogenesis; genetic deletion prevents cysts in mice (https://doi.org/10.1038/s41467-023-44410-9) (tham2024deletionofaurora pages 1-2). - BRAF–MEK–ERK; PI3K–AKT–mTOR: proliferative/growth pathways activated by cAMP and growth cues (https://doi.org/10.1038/s41467-023-44410-9; https://doi.org/10.3390/ijms25137173) (tham2024deletionofaurora pages 1-2, song2024reprogrammingofenergy pages 1-2). - Hippo effectors YAP1/WWTR1 (TAZ) and RHOA–MRTFA(MKL1)/SRF: proliferation–fibrosis coupling in cyst epithelium (https://doi.org/10.3390/cells13110984) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - STAT3: activated in cystic epithelia and inflammation networks (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - PDE3, AC5/6: cAMP compartmentalization and synthesis/breakdown influencing cystogenesis (Paolocci 2024 thesis) (paolocci2024campsignallingand pages 13-17, paolocci2024campsignallingand pages 1-7).

Chemical entities (CHEBI) - Calcium ion (CHEBI:29108); cAMP (CHEBI:17489); chloride ion (CHEBI:17996); glucose (CHEBI:17234); lactate (CHEBI:24996); vasopressin V2 receptor antagonist tolvaptan (drug; cAMP-lowering in ADPKD) (https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2).

Cell types (CL) - Renal tubular epithelial cells (collecting duct and nephron segments): cyst-lining epithelium (CL term category: epithelial cell) (https://doi.org/10.1038/s41467-023-44410-9; https://doi.org/10.3390/genes15010091) (tham2024deletionofaurora pages 1-2, satariano2024thepathophysiologyof pages 8-10). - Interstitial fibroblasts and myofibroblasts (CL: fibroblast lineage): ECM deposition (https://doi.org/10.3390/cells13110984) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - Macrophages (CL:0000235): inflammatory crosstalk, pro-fibrotic signaling (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10).

Anatomical locations (UBERON) - Kidney (parenchyma); renal tubule and collecting duct (cyst origin); interstitium; liver/biliary tree (ARPKD, polycystic liver disease) (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10).

Biological Processes (GO) disrupted - Cilium organization and ciliary signaling; mechanosensation; calcium ion homeostasis; cAMP signaling; chloride transport; MAPK cascade; PI3K–AKT–mTOR signaling; Hippo signaling; Wnt/PCP pathway; epithelial cell proliferation; epithelial fluid secretion; mitochondrial electron transport and fatty-acid β‑oxidation; extracellular matrix organization; inflammatory response and JAK–STAT cascade (https://doi.org/10.3390/genes15010091; https://doi.org/10.3390/ijms25137173; https://doi.org/10.3390/cells13110984; https://doi.org/10.1038/s41467-023-44410-9) (satariano2024thepathophysiologyof pages 8-10, song2024reprogrammingofenergy pages 1-2, lichner2024myocardinrelatedtranscriptionfactor pages 1-2, tham2024deletionofaurora pages 1-2).

Cellular Components (GO-CC) - Primary cilium, ciliary membrane, basal body; apical plasma membrane (CFTR); endoplasmic reticulum and mitochondrion (Ca2+ exchange and metabolism); extracellular region/extracellular matrix (https://doi.org/10.3390/genes15010091; https://doi.org/10.3390/ijms25137173) (satariano2024thepathophysiologyof pages 8-10, song2024reprogrammingofenergy pages 1-2).

Disease Progression (sequence of events) - Genetic lesion and second hit: germline PKD1/PKD2 (ADPKD) or PKHD1/DZIP1L (ARPKD) mutations with somatic inactivation in individual tubular cells initiate cysts (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - Cyst initiation: ciliary Ca2+ signaling failure increases cAMP; polarity/PCP cues are disturbed; early luminal fluid accumulation occurs via CFTR-mediated Cl− secretion (https://doi.org/10.3390/ijms25137173; https://doi.org/10.3390/genes15010091) (song2024reprogrammingofenergy pages 1-2, satariano2024thepathophysiologyof pages 8-10). - Cyst expansion: PKA–ERK and AKT–mTORC1 drive epithelial proliferation and growth; metabolic reprogramming supports biomass and energy; AURKA–AKT feed‑forward loop and Hippo/YAP amplify proliferation; RhoA–MRTF primes fibrosis (https://doi.org/10.1038/s41467-023-44410-9; https://doi.org/10.3390/ijms25137173; https://doi.org/10.3390/cells13110984) (tham2024deletionofaurora pages 1-2, song2024reprogrammingofenergy pages 1-2, lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - Tissue remodeling: interstitial inflammation and fibroblast activation produce fibrosis; nephron dropout and vascular rarefaction ensue, causing progressive GFR decline (https://doi.org/10.3390/genes15010091; https://doi.org/10.3390/cells13110984) (satariano2024thepathophysiologyof pages 8-10, lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - ARPKD distinctions: collecting-duct–predominant cysts with congenital hepatic fibrosis; fibrocystin C-terminal signaling restrains Src/STAT3 and secretory phenotypes in model systems, consistent with heightened STAT3 signaling when FPC is deficient (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10).

Phenotypic Manifestations (HP terms) - Renal cysts (HP:0000107), Enlarged kidneys (HP:0000105), Hypertension (HP:0000822), Hematuria (HP:0000790), Flank/abdominal pain; Hepatic cysts (HP:0001407) and congenital hepatic fibrosis (ARPKD); Intracranial aneurysm risk (HP:0002617). These manifestations reflect tubular cyst burden, interstitial fibrosis/inflammation, and systemic vascular/ductal involvement (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10).

Recent developments and latest research (2023–2024 priority) - AURKA–AKT feed‑forward loop as a master regulator: Aurka deletion prevented PKD across two genetic models; the data highlight non-kinase functions and caution that alisertib can stabilize AURKA in vivo, informing drug design (Nature Communications, 10 Jan 2024; https://doi.org/10.1038/s41467-023-44410-9) (tham2024deletionofaurora pages 1-2). - Human PKD1 cyst metabolic atlas: Systems biology analysis mapped a Warburg shift with predicted mTORC1/HIF‑1α/MYC activation and suppressed AMPK/PGC‑1α, concretizing metabolism-targeted therapies (IJMS, 26 Jun 2024; https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2). - Epithelial-initiated fibrogenesis: PKD epithelium activates RhoA–MRTF programs that prime myofibroblast transition, providing epithelial targets for anti-fibrotic intervention (Cells, 5 Jun 2024; https://doi.org/10.3390/cells13110984) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - ARPKD gene and pathway synthesis: Updated review integrates PKHD1/DZIP1L ciliary biology with EGFR/cAMP and ECM remodeling, clarifying pediatric hepato-renal disease mechanisms (Genes, 5 Jan 2024; https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - cAMP compartmentalization: New experimental work proposes PDE3 as a modulator of organelle cAMP nanodomains and potential PC2 interactor at ER–mitochondrial contacts (doctoral thesis, 2024) (paolocci2024campsignallingand pages 13-17, paolocci2024campsignallingand pages 1-7).

Current applications and implementations - Disease-modifying therapy: Tolvaptan (V2R antagonist) is approved to slow ADPKD progression by reducing cAMP; translational metabolism strategies (e.g., ketogenic interventions, AMPK activation) are supported by the human cyst metabolic signatures but require rigorous trials (https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2). - Emerging targets: AURKA–AKT axis, RhoA–MRTF signaling, Hippo/YAP, and cytokine–STAT3 pathways represent testable targets; the in vivo genetic validation of AURKA strengthens prioritization (https://doi.org/10.1038/s41467-023-44410-9; https://doi.org/10.3390/cells13110984) (tham2024deletionofaurora pages 1-2, lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

Expert opinions and analysis - 2024 syntheses argue that PKD integrates ciliary signaling failure with proliferative and metabolic rewiring; epithelial cells both initiate cystogenesis and act as paracrine organizers of interstitial fibrosis, implying dual-acting therapies that combine cAMP reduction, proliferation blockade, and anti-fibrotic reprogramming may be required for durable benefit (https://doi.org/10.3390/ijms25137173; https://doi.org/10.3390/cells13110984; https://doi.org/10.3390/genes15010091) (song2024reprogrammingofenergy pages 1-2, lichner2024myocardinrelatedtranscriptionfactor pages 1-2, satariano2024thepathophysiologyof pages 8-10).

Relevant statistics and data from recent studies - Genetic architecture: ADPKD due to PKD1 (~75–85%) or PKD2 (~15–25%); ARPKD due to PKHD1 with DZIP1L as a rarer cause/modifier (2024 review synthesis) (https://doi.org/10.3390/genes15010091) (satariano2024thepathophysiologyof pages 8-10). - Metabolic pathways: In human PKD1 cysts, gene sets for FAO, OXPHOS, BCAA degradation, and TCA cycle were downregulated, while glycolysis and lactate transporters were upregulated, aligning with predicted mTORC1/HIF‑1α/MYC activation and AMPK inhibition (IJMS 2024) (https://doi.org/10.3390/ijms25137173) (song2024reprogrammingofenergy pages 1-2). - In vivo mechanistic validation: Aurka deletion blocked cyst initiation and growth in two independent mouse PKD models and revealed AKT–AURKA physical interaction and a feed‑forward loop (Nature Communications 2024) (https://doi.org/10.1038/s41467-023-44410-9) (tham2024deletionofaurora pages 1-2).

Gene/protein annotations with ontology terms - HGNC: PKD1, PKD2, PKHD1, DZIP1L, CFTR, AURKA, BRAF, MAP2K1 (MEK1), MAPK1 (ERK2), PIK3CA, AKT1, MTOR, YAP1, WWTR1 (TAZ), RHOA, MRTFA (MKL1), SRF, STAT3, ADCY5/6, PDE3A/B (tham2024deletionofaurora pages 1-2, song2024reprogrammingofenergy pages 1-2, satariano2024thepathophysiologyof pages 8-10, lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - GO BP: cilium organization; calcium ion homeostasis; cAMP signaling; chloride transport; MAPK cascade; PI3K–AKT signaling; mTOR signaling; Hippo signaling; Wnt/PCP; epithelial cell proliferation; epithelial fluid secretion; mitochondrial electron transport chain; fatty acid β-oxidation; extracellular matrix organization; inflammatory response; JAK–STAT cascade (tham2024deletionofaurora pages 1-2, song2024reprogrammingofenergy pages 1-2, satariano2024thepathophysiologyof pages 8-10, lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - GO CC: primary cilium; ciliary membrane; basal body; apical plasma membrane; endoplasmic reticulum; mitochondrion; extracellular matrix (song2024reprogrammingofenergy pages 1-2, satariano2024thepathophysiologyof pages 8-10).

Phenotype associations (HP terms) - Renal cysts (HP:0000107); Enlarged kidneys (HP:0000105); Hypertension (HP:0000822); Hematuria (HP:0000790); Hepatic cysts (HP:0001407); Intracranial aneurysm (HP:0002617) (satariano2024thepathophysiologyof pages 8-10).

Cell type involvement (CL terms) - Renal tubular epithelial cell (cyst-lining); fibroblast/myofibroblast; macrophage (tham2024deletionofaurora pages 1-2, satariano2024thepathophysiologyof pages 8-10, lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

Anatomical locations (UBERON terms) - Kidney; renal tubule; collecting duct; renal interstitium; liver/biliary tree (satariano2024thepathophysiologyof pages 8-10).

Chemical entities (CHEBI) - Calcium ion; cAMP; chloride ion; glucose; lactate; tolvaptan (drug) (song2024reprogrammingofenergy pages 1-2).

Evidence items (PMIDs/DOIs and dates) - Tham et al., Nature Communications, 10 Jan 2024. “Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice.” https://doi.org/10.1038/s41467-023-44410-9 (tham2024deletionofaurora pages 1-2). - Song et al., International Journal of Molecular Sciences, 26 Jun 2024. “Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease.” https://doi.org/10.3390/ijms25137173 (song2024reprogrammingofenergy pages 1-2). - Lichner et al., Cells, 5 Jun 2024. “Myocardin-Related Transcription Factor Mediates Epithelial Fibrogenesis in PKD.” https://doi.org/10.3390/cells13110984 (lichner2024myocardinrelatedtranscriptionfactor pages 1-2). - Satariano et al., Genes, 5 Jan 2024. “The Pathophysiology of Inherited Renal Cystic Diseases.” https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10). - Paolocci E., 2024 thesis. “cAMP signalling and phosphodiesterase activity in cystogenesis of ADPKD.” (paolocci2024campsignallingand pages 13-17, paolocci2024campsignallingand pages 1-7).

Summary artifact | Mechanistic domain | Key findings (1–2 sentences) | Principal molecules/genes | Cell types | 2023–2024 sources (journal, year, URL/DOI) | |---|---|---|---|---| | Ciliary dysfunction & mechanotransduction | Loss or dysfunction of PC1/PC2 in primary cilia impairs ciliary Ca2+ mechanosensing, disrupting downstream signaling and promoting cyst initiation; somatic "second hits" in cysts are common. | PKD1 (PC1), PKD2 (PC2), IFT/KIF genes | Renal tubular epithelial cells (collecting duct, nephron epithelia) | Nature Communications, 2024, https://doi.org/10.1038/s41467-023-44410-9 (tham2024deletionofaurora pages 1-2); Genes, 2024, https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10) | | Ca2+/cAMP and CFTR-mediated Cl- secretion | Reduced intraciliary/cytosolic Ca2+ disinhibits adenylyl cyclases increasing cAMP; cAMP/PKA promotes epithelial proliferation and CFTR-mediated chloride/fluid secretion that expands cysts; V2R antagonism (tolvaptan) lowers cAMP clinically. | AC5/6, cAMP, PDE3, CFTR, AVPR2 (V2R) | Cyst-lining epithelial cells | Unknown journal, 2024 (Paolocci thesis) (paolocci2024campsignallingand pages 13-17); IJMS, 2024, https://doi.org/10.3390/ijms25137173 (song2024reprogrammingofenergy pages 1-2) | | Proliferative signaling (MAPK/ERK, PI3K/AKT/mTOR) | cAMP/PKA and growth-receptor signaling activate B-Raf→MEK→ERK and PI3K→AKT→mTORC1, driving cell cycle entry, growth and metabolic programs that sustain cyst growth. | BRAF/MEK/ERK, PI3K, AKT, mTOR, c-MYC | Tubular epithelial cells (cyst epithelium) | Nature Communications, 2024, https://doi.org/10.1038/s41467-023-44410-9 (tham2024deletionofaurora pages 1-2); IJMS, 2024, https://doi.org/10.3390/ijms25137173 (song2024reprogrammingofenergy pages 1-2) | | Hippo — YAP/TAZ | Dysregulated Hippo signaling permits nuclear YAP/TAZ activity, promoting transcriptional programs (e.g., c-MYC) that increase proliferation and link to fibrogenic responses. | YAP, TAZ, LATS1/2, MST1/2 | Cyst-lining epithelial cells; epithelial progenitors | Cells, 2024, https://doi.org/10.3390/cells13110984 (lichner2024myocardinrelatedtranscriptionfactor pages 1-2); Genes, 2024, https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10) | | Wnt / Planar cell polarity (PCP) | Defects in Wnt/PCP signaling disrupt oriented cell division and tubule architecture, contributing to abnormal tubule dilation and cyst formation. | WNT ligands, VANGL/CELSR, DVL | Tubular epithelial cells | Genes, 2024, https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10) | | Metabolic reprogramming & mitochondria | Cystic epithelia show a Warburg-like shift (↑glycolysis, ↑lactate) with suppressed FAO and OXPHOS, AMPK inhibition and mTOR activation, supporting proliferation and survival. | GLUTs, HK1/2, LDHA, PDK1, AMPK, PGC‑1α | Cyst-lining epithelial cells | IJMS, 2024, https://doi.org/10.3390/ijms25137173 (song2024reprogrammingofenergy pages 1-2) | | Inflammation & immune (JAK/STAT, cytokines) | Immune cell infiltration and cytokine dysregulation (e.g., IL‑family) activate JAK/STAT and NF‑κB pathways, amplifying epithelial proliferation and fibrotic remodeling. | IL family (IL‑12/23), JAK/STAT3, NF‑κB, STING, TWEAK/Fn14 | Macrophages, epithelial cells, fibroblasts | Genes, 2024, https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10); Cells, 2024, https://doi.org/10.3390/cells13110984 (lichner2024myocardinrelatedtranscriptionfactor pages 1-2) | | ECM remodeling & fibrosis (MRTF; fibroblast–macrophage crosstalk) | Epithelial RhoA activation drives MRTF nuclear translocation and profibrotic gene expression, priming fibroblast→myofibroblast transition; reciprocal Wnt–macrophage–fibroblast crosstalk promotes interstitial fibrosis. | RHOA, MRTF‑A/B, SRF, collagen, TGF‑β, WNT | Tubular epithelial cells, interstitial fibroblasts, macrophages | Cells, 2024, https://doi.org/10.3390/cells13110984 (lichner2024myocardinrelatedtranscriptionfactor pages 1-2); Genes, 2024, https://doi.org/10.3390/genes15010091 (satariano2024thepathophysiologyof pages 8-10) | | Cell cycle / ciliogenesis regulators (AURKA) | AURKA is upregulated in PKD, promotes proliferation and ciliary disassembly and forms a feed‑forward loop with AKT; genetic deletion of Aurka prevents cyst formation in mouse PKD models. | AURKA, AKT | Collecting-duct and tubular epithelial cells | Nature Communications, 2024, https://doi.org/10.1038/s41467-023-44410-9 (tham2024deletionofaurora pages 1-2) |

Table: Compact 2023–2024 evidence map summarizing major molecular/cellular mechanisms in ADPKD/ARPKD, with principal genes, affected cell types, and primary sources; useful as a quick reference linking mechanisms to recent literature (context citations included).

Direct quotes supporting key statements - “Deletion of the Aurora Kinase A gene… prevents cyst formation in both disease models… AURKA and AKT physically interact… creating a feed-forward loop driving renal cystogenesis.” (Nature Communications, 2024) (tham2024deletionofaurora pages 1-2). - “Gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect… mitochondrial energy metabolism was globally depressed… activation of mTORC1 and… HIF-1α and MYC… AMPK inhibition was predicted in renal cysts.” (IJMS, 2024) (song2024reprogrammingofenergy pages 1-2). - “The loss of PC1 or PC2… activated RhoA… robust nuclear MRTF translocation… epithelial MRTF was necessary for the paracrine priming of the fibroblast–myofibroblast transition.” (Cells, 2024) (lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

Conclusion PKD pathogenesis is best understood as an integrated network linking primary-cilium dysfunction and Ca2+/cAMP derangements to proliferative signaling, metabolic reprogramming, and fibrotic/inflammatory remodeling. Recent 2024 studies provide in vivo mechanistic validation (AURKA–AKT) and human cyst metabolic maps (Warburg shift), while epithelial RhoA–MRTF signaling emerges as a nexus between cystogenesis and fibrosis. These insights nominate combined strategies—precise cAMP modulation, anti-proliferative pathway inhibition, and anti-fibrotic reprogramming—as rational avenues to slow disease progression beyond current V2R antagonism (https://doi.org/10.1038/s41467-023-44410-9; https://doi.org/10.3390/ijms25137173; https://doi.org/10.3390/cells13110984) (tham2024deletionofaurora pages 1-2, song2024reprogrammingofenergy pages 1-2, lichner2024myocardinrelatedtranscriptionfactor pages 1-2).

References

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  4. (paolocci2024campsignallingand pages 13-17): E Paolocci. Camp signalling and phosphodiesterase activity in cystogenesis of autosomal dominant polycystic kidney disease. Unknown journal, 2024.

  5. (paolocci2024campsignallingand pages 1-7): E Paolocci. Camp signalling and phosphodiesterase activity in cystogenesis of autosomal dominant polycystic kidney disease. Unknown journal, 2024.

  6. (lichner2024myocardinrelatedtranscriptionfactor pages 1-2): Zsuzsanna Lichner, Mei Ding, Tarang Khare, Qinghong Dan, Raquel Benitez, Mercédesz Praszner, Xuewen Song, Rola Saleeb, Boris Hinz, York Pei, Katalin Szászi, and András Kapus. Myocardin-related transcription factor mediates epithelial fibrogenesis in polycystic kidney disease. Cells, 13:984, Jun 2024. URL: https://doi.org/10.3390/cells13110984, doi:10.3390/cells13110984. This article has 4 citations and is from a poor quality or predatory journal.