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Review

Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease

1
Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43614, USA
2
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2025, 14(15), 1203; https://doi.org/10.3390/cells14151203
Submission received: 26 June 2025 / Revised: 31 July 2025 / Accepted: 1 August 2025 / Published: 5 August 2025

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

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MDPI and ACS Style

Al-orjani, Q.; Alshriem, L.A.; Gallagher, G.; Buqaileh, R.; Azizi, N.; AbouAlaiwi, W. Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease. Cells 2025, 14, 1203. https://doi.org/10.3390/cells14151203

AMA Style

Al-orjani Q, Alshriem LA, Gallagher G, Buqaileh R, Azizi N, AbouAlaiwi W. Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease. Cells. 2025; 14(15):1203. https://doi.org/10.3390/cells14151203

Chicago/Turabian Style

Al-orjani, Qasim, Lubna A. Alshriem, Gillian Gallagher, Raghad Buqaileh, Neela Azizi, and Wissam AbouAlaiwi. 2025. "Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease" Cells 14, no. 15: 1203. https://doi.org/10.3390/cells14151203

APA Style

Al-orjani, Q., Alshriem, L. A., Gallagher, G., Buqaileh, R., Azizi, N., & AbouAlaiwi, W. (2025). Mechanistic Insights into the Pathogenesis of Polycystic Kidney Disease. Cells, 14(15), 1203. https://doi.org/10.3390/cells14151203

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