, Volume 23, Issue 4, pp 203-216
Date: 16 Aug 2012

Therapeutic Potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitors in Polycystic Kidney Disease

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

In the common genetic disorder autosomal dominant polycystic kidney disease (ADPKD), kidney function is disrupted by multiple fluid-filled epithelial cysts. Cyst growth in ADPKD involves fluid accumulation within the cyst lumen driven by cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial Cl secretion. This suggests that inhibitors of the CFTR Cl channel might retard cyst growth. This review considers how knowledge of CFTR structure and function and its role in transepithelial salt and water movements provides insight into the mechanism of action of CFTR inhibitors. Some small molecules, termed open-channel blockers, inhibit directly the CFTR Cl channel by physically obstructing the CFTR pore and preventing Cl flow. By contrast, other small molecules, termed allosteric inhibitors, bind to CFTR at a site remote from the channel pore and interfere with conformational changes that open the pore. The application of high-throughput screening to CFTR drug discovery has led to the identification of new inhibitors of the CFTR Cl channel including the thiazolidinone CFTRinh-172 and the glycine hydrazide GlyH-101. The demonstration that CFTR inhibitors retard cyst expansion and kidney enlargement in mouse models of ADPKD provides proof of concept for the use of small-molecule CFTR inhibitors in the treatment of ADPKD.