@article{9f0b3bb899144e7d82dc400e7b34b068,
title = "Treatment prospects for autosomal-dominant polycystic kidney disease",
abstract = "Treatment prospects for autosomal-dominant polycystic kidney disease. An increased understanding of the molecular genetic and cellular pathophysiologic mechanisms responsible for the development of autosomal-dominant polycystic kidney disease (ADPKD), made possible by the advances in molecular biology and genetics of the last three decades, has laid the foundation for the development of effective therapies. As the concept that a polycystic kidney is a neoplasm in disguise is becoming increasingly accepted, the development of therapies for ADPKD may benefit greatly from the expanding body of information on cancer chemoprevention and chemosuppression. This review summarizes the observations that already have been made and discusses therapies for PKD that deserve investigation.",
keywords = "Antimutagens, Antioxidants, EGF receptor, Fish oil, Soy protein, Tyrosine kinase inhibitors",
author = "Qi Qian and Harris, {Peter C.} and Torres, {Vicente E.}",
note = "Funding Information: By the time the renal cysts reach a diameter of approximately 2 mm, they become disconnected from the tubular segment from which they derived. Further growth of the cysts depends on a process of transepithelial fluid secretion. The driving force is an active transport of chloride from the basolateral to the apical side. The potential energy for chloride secretion is developed by the sodium pump (Na + ,K + -ATPase) located in the basolateral membranes of cyst epithelial cells. The chloride entry mechanism into the basolateral membrane is a sodium-potassium-chloride, bumetanide-sensitive, cotransporter (NKCC1 or BSC2), which utilizes the gradient established by the sodium pump to bring K and Cl into the cells. Net chloride transport is accomplished by opening chloride channels within the apical membrane. Chloride ions flow down an electrochemical gradient into the cyst generating increased transepithelial electron activity that in turn drives sodium ions through ion selective paracellular pathways. An apical chloride channel that may play a role in cyst fluid accumulation is the cystic fibrosis transmembrane conductance regulator (CFTR). This is supported by the up-regulation of CFTR in some cysts, by whole cell patch clamp studies of ADPKD-derived epithelial cells, by the CFTR antisense oligonucleotide-induced inhibition of fluid secretion in cyst-derived cell monolayers, and by the observation of a milder cystic phenotype in two patients affected by both ADPKD and cystic fibrosis 119 . On the other hand, attenuation of the cystic phenotype was not observed in a third patient with ADPKD and cystic fibrosis (abstract; Persu A, 33rd ASN Meeting , 2000) and CFTR does not seem to be important in the autosomal recessive murine orpk model of cystic disease (abstract; Nakanishi T, 33rd ASN Meeting , 2000). The activation of the NKCC1/BSC2 cotransporter and of the chloride channels is regulated by PKA-mediated phosphorylation, which is under hormonal control. The secretion of chloride and fluid by cyst-derived epithelial cells is stimulated by a number of agonists that stimulate the production of cAMP, such as vasopressin, secretin, vasoactive intestinal peptide, prostaglandin E1 and E2, and cyst activating factor (CAF). Secretin has been shown to increase the rate of fluid secretion in vivo in renal and hepatic cysts of subjects with ADPKD 120 . In addition, testosterone has been found to activate adenylcyclase, increase cellular cAMP, and stimulate the secretion of chloride and fluid by monolayers of MDCK cells, possibly contributing to the gender dimorphism observed in human ADPKD and rat models of PKD 121 . Funding Information: Grant support was provided by the National Institutes of Health Grant DK44863.",
year = "2001",
doi = "10.1046/j.1523-1755.2001.0590062005.x",
language = "English (US)",
volume = "59",
pages = "2005--2022",
journal = "Kidney international",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "6",
}