Molecular pathways and therapies in autosomal-dominant polycystic kidney disease

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.

FIGURE 1.

Activation of intrarenal RAS in PKD Cystic expansion may compress arterioles in the kidney, triggering renin release from Juxtaglomerular apparatus (JGA) and increased angiotensin II (AngII), causing vasoconstriction and elevated BP. In kidney, cystic fluid and cyst lining cells have Agt, renin, and AngII. Since proximal tubules are abundant with Agt, it is possible that Agt-mediated angII production may stimulate cyst growth and increase downstream Na⁺ reabsorption at the distal/collecting duct, resulting in salt retention. Mutation in PKD1 and PKD2 has been linked with altered vasculature and vascular response to shear stress, reduced nitric oxide production, which may also contribute to elevated BP.

FIGURE 2.

Potential factors that lead to progression of cyst formation in APDKD A: cysts are derived from a single cell (monoclonal) that develops with a second hit (somatic mutation) of the remaining allele of PKD1 or PKD2. B: graph showing an example of GFR and cyst progression in mild (top) vs. severe (bottom) renal cystic phenoptype in ADPKD. Third hits and incomplete penetration of mutated PKD gene may help explain severity and rate of cystic growth (arrow).