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Genetic and Kidney Cyst Diseases · Review
BMC Nephrology · August 24, 2026
Raises a question worth testing. It does not answer one.
This narrative review synthesizes translational and experimental evidence from multiple PKD model systems to map signaling pathways implicated in cyst initiation and progression, and identifies candidate therapeutic targets (vasopressin antagonists, microRNA therapeutics, metabolic modulators, and combination approaches). The work is conceptual and hypothesis-generating rather than reporting confirmatory clinical or even definitive preclinical efficacy data, and is intended to frame future therapeutic development.
Narrative review. Literature on PKD models and signaling mechanisms; no human subjects enrolled..
Disease progression regulated by complex interconnected signaling networks arising from dysregulation across multiple pathways, not solely monogenic mutation. Cyst initiation and progression arise from convergent defects in mechanosensation, epithelial proliferation, metabolic reprogramming, innate immune activation, and fibrotic remodeling. Therapeutic targets identified include vasopressin–cyclic AMP signaling, mTOR and AMPK pathways, Hippo–YAP/TAZ mechanotransduction, cGAS–STING inflammatory axis, microRNA networks, and gut–kidney axis.
No primary efficacy or safety data from human trials reported.
This review identifies mechanistic insights and therapeutic candidates for PKD but does not report clinical trial efficacy or safety data. Clinicians should regard identified pathways and drug candidates as targets for future rigorous translational and clinical testing, not as evidence supporting current practice changes.
This is a narrative review synthesizing experimental and translational findings across multiple model systems; it raises mechanistic questions and identifies therapeutic targets rather than reporting clinical trial results or definitive evidence from human studies.
As stated by the source record.
This review identifies mechanistic insights and therapeutic candidates for PKD but does not report clinical trial efficacy or safety data. Clinicians should regard identified pathways and drug candidates as targets for future rigorous translational and clinical testing, not as evidence supporting current practice changes.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Polycystic kidney disease (PKD) has undergone a major conceptual reappraisal over the past decade. Although PKD is fundamentally a monogenic disorder caused by mutations in PKD1, PKD2, PKHD1, and related genes, it is now increasingly recognized that disease progression is regulated by complex and interconnected signaling networks arising from coordinated dysregulation across multiple regulatory pathways. Advances in experimental models, multi-omics technologies, and cross-species approaches have revealed that cyst initiation and progression arise from convergent defects in mechanosensation, epithelial proliferation, metabolic reprogramming, innate immune activation, and fibrotic remodeling. In this Review, we synthesize insights from genetically engineered mouse models, naturally occurring rodent strains, CRISPR/Cas9-based large-animal systems, and human cell–derived spheroids and induced pluripotent stem cell (iPSC)–derived kidney organoids. We highlight how conditional knockout platforms define the spatial and temporal origins of cystogenesis, whereas hypomorphic and allele-specific models clarify mutation- and dosage-dependent determinants of disease severity. These complementary systems connect upstream polycystin dysfunction to downstream therapeutic hubs, including vasopressin–cyclic AMP signaling, mTOR and AMPK pathways, Hippo–YAP/TAZ mechanotransduction, the cGAS–STING inflammatory axis, microRNA regulatory networks, and the gut–kidney axis. We further discuss how pathway-informed testing across model systems has accelerated the development of mechanism-based interventions, including vasopressin V2 receptor antagonists, nucleic acid–based microRNA therapeutics, metabolic modulators, kidney-targeted drug-delivery strategies, and rational combination therapies. Finally, we outline emerging directions for network-informed and stage-specific treatment strategies, emphasizing lineage-resolved targeting and translational validation in large-animal and human-derived platforms. This integrated framework provides a foundation for future therapies aimed at modifying the natural history of PKD. Clinical trial number Not applicable.
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