A ROLE FOR CFTR IN HUMAN AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Human autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal dominant hereditary disorder characterized by enormous renal enlargement and the development of multiple cysts originating fr om nephrons. We investigated the pathogenesis of cyst formation in ADP KD by using patch-clamp and immunocytochemical techniques. Adenosine 3 ',5'-cyclic monophosphate-activated Cl- currents are present in primar y cultures of ADPKD cells and have characteristics such as a linear cu rrent-voltage relation, insensitivity to 4,4'-diisothiocyanostilbene-2 ,2'-disulfonic acid, sensitivity to glibenclamide and diphenylamine ca rboxylic acid, and an anion selectivity sequence of Br- > Cl- > I- > g lutamate, all of which are identical to cystic fibrosis transmembrane conductance regulator (CFTR). With the use of CFTR antibodies raised a gainst the regulatory and first nucleotide-binding domains, CFTR was d etected in primary cultures of ADPKD cells. Similar results were obtai ned in vivo in cyst-lining epithelial cells in ADPKD kidneys, where st aining was seen associated with the apical membrane regions. These dat a indicate that the CFTR Cl- channel exists in apical membranes ofADPK D cells and may play an important role in cyst formation or enlargemen t.