Epithelial Transport in Polycystic Kidney Disease

Abstract

In autosomal dominant polycystic kidney disease (ADPKD), the genetic defect results in the slow growth of a multitude of epithelial cysts within the renal parenchyma. Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts. The majority of cysts disconnect from tubular structures as they grow but still accumulate fluid within the lumen. The fluid accumulation is the result of secretion of fluid driven by active transepithelial Cl- secretion. Proliferation of the cells and fluid secretion are activated by agonists of the cAMP signaling pathway. The transport mechanisms involved include the cystic fibrosis transmembrane conductance regulator (CFTR) present in the apical membrane of the cystic cells and a bumetanide-sensitive transporter located in the basolateral membrane. A lipid factor, called cyst activating factor, has been found in the cystic fluid. Cyst activating factor stimulates cAMP production, proliferation, and fluid secretion by cultured renal epithelial cells and also is a chemotactic agent. Cysts also appear in the intrahepatic biliary tree in ADPKD. Normal ductal cells secrete Cl- and HCO3-. The cystic ductal cell also secretes Cl-, but HCO3- secretion is diminished, probably as the result of a lower population of Cl-/HCO3- exchangers in the apical membrane as compared with the normal cells. Some segments of the normal renal tubule are also capable of utilizing CFTR to secrete Cl-, particularly the inner medullary collecting duct. The ability of Madin-Darby canine kidney cells and normal human kidney cortex cells to form cysts in culture and to secrete fluid and the functional similarities between these incompletely differentiated, proliferative cells and developing cells in the intestinal crypt and in the fetal lung have led us to suggest that Cl- and fluid secretion may be a common property of at least some renal epithelial cells in an intermediate stage of development. The genetic defect in ADPKD may not directly affect membrane transport mechanisms but rather may arrest the development of certain renal epithelial cells in an incompletely differentiated, proliferative stage.

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

“…Therefore, under physiologic conditions, endogenous ouabain can readily activate the MEK-ERK pathway in the cyst cells of ADPKD kidneys, representing a factor that may have a direct impact on the growth of the cysts. A variety of circulating factors, hormones, and autocoids have been shown to stimulate the proliferation of renal cyst epithelial cells (21,27,(23)(24)(25)48,49). This study is the first to demonstrate that ouabain, an endogenous steroid hormone, has a positive effect on proliferation of ADPKD cells.…”

“…When the cells were grown to confluence on filter supports, cell polarity of the cultures was confirmed by the achievement of a transepithelial electrical resistance by the cell monolayer, measured with an EVOM volt ohmmeter (World Precision Instruments, Sarasota, FL) as described previously (31). In culture, both ADPKD and NHK cells are able to establish a monolayer, form tight junctional complexes, and develop a transepithelial electrical potential difference, and they carry out an active transepithelial transport of salt and fluid (27,30,32). As previously shown, these cells are epithelial in nature, and the majority of the cells stain positive for specific lectin markers for the collecting duct and distal nephron, such as Arachis hypogaea and Dolichos biflorus agglutinin (26).…”

“…cAMP causes cell proliferation in human cells and animal models of PKD, also via the MEK-ERK pathway, through B-Raf, a kinase that phosphorylates and activates MEK (25,26). In addition, cyst expansion is the result of transepithelial fluid secretion that is driven by the cAMP-dependent secretion of Cl Ϫ (27). Because of its central role in salt and water transport, the Na,K-ATPase has been the focus of investigation to understand the pathophysiology of PKD (17).…”

Cell biology of polycystin-2

“…However, if we assume that the primary defect in type 2 ADPKD is PKD2-mediated Ca 2+ influx (and not Na + or K + which also pass through PKD2), it is possible that a connection between a Ca 2+ channel and cAMP can be made. It has been reported that cystic cells have abnormally high levels of cAMP [79][80][81][82] and the administration of a vasopressin V2 receptor antagonist, which reduced cAMP, suppressed the cystic phenotype in PKD2 knock out mice [83] and other animal models [84,85]. It is also known that store-operated Ca 2+ channels are directly coupled to specific isoforms of adenylyl cyclases [86][87][88].…”

Phloxine B Interacts with the Cystic Fibrosis Transmembrane Conductance Regulator at Multiple Sites to Modulate Channel Activity

“…Other diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and secretory diarrhea, likely involve increased activity of the CFTR Cl Ϫ channel (5,6). ADPKD affects more than 1 in 1000 live births and is the most common single gene defect associated with the loss of kidney function (5). Secretory diarrhea annually kills millions of infants in Africa, Asia, and Latin America (7).…”