Pathogenic Pathways and Therapeutic Strategies in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of end-stage renal disease. The disorder is primarily caused by pathogenic variants in PKD1 or PKD2, which encode the ciliary proteins polycystin-1 and polycystin-2. Loss of polycystin function disrupts calcium and cAMP signaling within the primary cilium, altering epithelial proliferation and fluid secretion that drive cyst formation and progressive kidney enlargement. Atypical forms of ADPKD arise from variants in genes required for the production of polycystins or for ciliary assembly. Cyst growth depends on proliferative and secretory pathways involving Ca²⁺, cAMP, mTORC1, Src, and receptor tyrosine kinases, while chloride and water transport via CFTR, ANO1, and NKCC1 drive luminal expansion. The vasopressin V2 receptor antagonists tolvaptan remains the only approved therapy, but new approaches are under investigation. These include inhibitors of mTORC1, Src, and RTKs, agents that block chloride secretion, small molecules and microRNAs that restore or enhance polycystin expression, and emerging cyst-directed cytotoxic therapies. By targeting aberrant epithelial responses to disrupted polycystin function, therapeutic intervention can be developed to halt cyst initiation, expansion, and progression to renal failure.