Cellular pathophysiology of cystic kidney disease: insight into future therapies

Polycystic kidney disease (PKD) is a developmental kidney disorder which ca n be inherited as either an autosomal dominant trait, with an incidence of 1:50 to 1:1000, or as an autosomal recessive trait with an incidence of 1:6 ,000 to 1:40,000. Three different genes have now been cloned that are assoc iated with mutations that cause PKD. Two of these are linked to the most co mmon forms of the dominant disease while the third is associated with the o rpk mouse model of recessive polycystic kidney disease. Advances in underst anding the molecular genetics of PKD have been paralleled by new insights i nto the cellular pathophysiology of cyst formation and progressive enlargem ent. Current data suggest that a number of PKD proteins may interact in a c omplex, which when disrupted by mutations in PKD genes may lead to altered epithelial proliferative activity, secretion, and cell matrix biology. The identification of a unique cystic epithelial phenotype presents new opportu nities for targeted therapies. These include targeted gene therapy, gene co mplementation, and specific immunological or pharmacological interruption o f growth factor pathways.