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

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a leading cause of end-stage renal disease.
• Pathogenic variants in PKD1 or PKD2, encoding ciliary proteins polycystin-1 and polycystin-2, are the primary cause of ADPKD.
• Disrupted polycystin function affects intracellular signaling, leading to epithelial cell proliferation and fluid secretion, driving cyst formation and kidney enlargement.

Purpose of the Study:

• To review the molecular mechanisms underlying ADPKD pathogenesis.
• To explore current and emerging therapeutic strategies targeting cyst growth pathways.
• To highlight the potential for novel treatments to halt disease progression.

Main Methods:

• Review of scientific literature on ADPKD genetics, pathophysiology, and therapeutic targets.
• Analysis of signaling pathways involved in cyst initiation, growth, and progression.
• Evaluation of existing and experimental therapeutic interventions.

Main Results:

• ADPKD pathogenesis involves disrupted calcium and cAMP signaling within primary cilia due to polycystin dysfunction.
• Cyst growth is driven by proliferative pathways (mTORC1, Src, RTKs) and secretory pathways (CFTR, ANO1, NKCC1).
• Tolvaptan is the only approved therapy; emerging treatments target these pathways, including inhibitors and gene/protein restoration strategies.

Conclusions:

• Targeting aberrant epithelial responses to disrupted polycystin function offers a promising therapeutic avenue for ADPKD.
• Interventions can potentially halt cyst initiation, expansion, and progression to renal failure.
• Further research into cyst-directed therapies is crucial for improving patient outcomes in ADPKD.