Role of CFTR in autosomal recessive polycystic kidney disease

An extensive body of in vitro data implicates epithelial chloride secretion , mediated through cystic fibrosis transmembrane conductance regulator (CFT R) protein, in generating or maintaining fluid filled cysts in MDCK cells a nd in human autosomal dominant polycystic kidney disease (ADPKD). In contra st, few studies have addressed the pathophysiology of fluid secretion in cy st formation and enlargement in autosomal recessive polycystic kidney disea se (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene pro ducts in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the op portunity to determine whether CFTR activity is required for renal cyst for mation in vivo. Therefore, this study sought to determine whether renal cys t formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study rev eal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlar ged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/+/-). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADP KD.