title: cAMP-dependent protein kinase and proliferation differ in normal and polycystic kidney epithelia.
abstract: Developmental control of cell proliferation is crucial, and abnormal principal cell proliferation may contribute to cystogenesis in polycystic kidney disease. This study investigates roles of cAMP and its primary effector, cAMP-dependent protein kinase (protein kinase A; PKA), in control of cell proliferation in filter-grown noncystic (NC) and cystic (CY)-derived principal cell cultures. These cultures had similar cAMP pathway characteristics upstream of PKA subunit distribution but differed in predicted PKA subtype distribution. Functionally, cultures were proliferative before polarization, with constitutively higher proliferation in CY cultures. NC cultures achieved levels similar to those of CY cultures on pharmacological manipulation of cAMP production or PKA activation or inhibition of PKA subtype I activity. Inhibition of overall PKA activity, or of PKA subtype II anchoring, diminished cAMP/PKA-mediated proliferation in NC cultures but had no effect on CY cultures. Polarized CY monolayers remained proliferative, but NC monolayers lost responsiveness. No large proliferation changes resulted from treatments of polarized cultures; however, polarized NC and CY cultures differed in poststimulation handling of PKA catalytic and type IIalpha regulatory subunits. Our results support PKA subtype regulation of prepolarization proliferation in NC principal cells and altered regulation of PKA in CY cells and suggest that differences at or downstream of PKA can contribute to altered proliferation in a developmental renal disease.
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-6003.
authors.forename: Carmela
authors.initials: C
authors.lastname: Marfella-Scivittaro
authors.forename: Andrea
authors.initials: A
authors.lastname: Quiñones
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Orellana
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D066246:ErbB Receptors / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011799:Quinazolines; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; C118029:CL 387785; D000242:Cyclic AMP; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide