Modulation of cyst growth in autosomal dominant polycystic kidney disease: mechanistic insights and therapeutic opportunities
Ursu R, Buchholz B, Skoczynski K (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: 331
Journal Issue: 3
DOI: 10.1152/ajpcell.00222.2026
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney disorders and is characterized by the progressive formation and expansion of fluid-filled cysts, ultimately leading to kidney failure. Although caused by reduced dosage of the polycystin proteins, the disease phenotype arises from a broad disruption of epithelial physiology rather than a single linear pathway. Loss of polycystin function destabilizes epithelial homeostasis and sensitizes cyst-lining cells to proliferative and secretory cues. A central consequence is the emergence of a self-reinforcing signaling environment in which cyclic AMP, Ca2 þ , and purinergic pathways amplify one another, promoting chloride-driven fluid secretion and epithelial proliferation. In parallel, cyst epithelia exhibit disturbed cell turnover, including altered proliferation, apoptosis, autophagy, and ferroptotic stress, which reshape luminal architecture and sustain a prosecretory microenvironment. Metabolic reprogramming, characterized by enhanced glycolysis, mitochondrial dysfunction, and redox imbalance, provides energetic support for these processes and further strengthens proliferative and secretory signaling. Hypoxia-inducible factor-1a (HIF-1a) integrates hypoxic, metabolic, and mechanical cues into transcriptional programs that reinforce cyst expansion. This review synthesizes these interconnected mechanisms and highlights potential therapeutic strategies, including restoration of polycystin expression, modulation of cAMP and purinergic signaling, inhibition of chloride secretion, metabolic targeting, and HIF-1a pathway intervention. Together, these insights support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs. Effective disease modification will likely require multinodal therapeutic approaches that address this integrated network.
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APA:
Ursu, R., Buchholz, B., & Skoczynski, K. (2026). Modulation of cyst growth in autosomal dominant polycystic kidney disease: mechanistic insights and therapeutic opportunities. American Journal of Physiology-Cell Physiology, 331(3). https://doi.org/10.1152/ajpcell.00222.2026
MLA:
Ursu, Raluca, Bjoern Buchholz, and Kathrin Skoczynski. "Modulation of cyst growth in autosomal dominant polycystic kidney disease: mechanistic insights and therapeutic opportunities." American Journal of Physiology-Cell Physiology 331.3 (2026).
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