Small‐Molecule CFTR Inhibitors Slow CYST Growth in Culture and Mouse Models of Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a major cause of chronic renal insufficiency. Cyst expansion in PKD involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The Aim of this study is to test if small‐molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. Screening of more than 30 CFTR inhibitor analogs in an MDCK cell cyst model indicated near complete suppression of cyst growth by the tetrazolo‐derivatized thiazolidinone, tetrazolo‐CFTRinh‐172, and the phenyl‐derivatized glycine hydrazide, Ph‐GlyH‐101, without effect on cell proliferation. These compounds also inhibited cyst number and growth by > 80 % in an embryonic kidney cyst model involving 4‐day organ culture of E13.5 mouse kidneys in 8‐Br‐cAMP‐containing medium. Subcutaneous delivery of tetrazolo‐CFTRinh‐172 and Ph‐GlyH‐101 to neonatal, kidney‐specific PKD1 knock‐out mice produced stable and ‘therapeutic’ inhibitor concentrations of >3 μM in urine and kidney tissue. Treatment of mice for up to 7 days remarkably slowed kidney enlargement and cyst expansion, and preserved renal function. These results indicate the involvement of CFTR in renal cyst growth in PKD, and provide proof‐of‐concept for application of CFTR inhibitors to reduce cyst growth in PKD.