cAMP-dependent protein kinase and proliferation differ in normal and polycystic kidney epithelia

Developmental control of cellproliferation is crucial, and abnormal principal cell proliferation maycontribute to cystogenesis in polycystic kidney disease. This studyinvestigates roles of cAMP and its primary effector, cAMP-dependentprotein kinase (protein kinase A; PKA), in control of cellproliferation in filter-grown noncystic (NC) and cystic (CY)-derivedprincipal cell cultures. These cultures had similar cAMP pathwaycharacteristics upstream of PKA subunit distribution but differed inpredicted PKA subtype distribution. Functionally, cultures wereproliferative before polarization, with constitutively higherproliferation in CY cultures. NC cultures achieved levels similar tothose of CY cultures on pharmacological manipulation of cAMP productionor PKA activation or inhibition of PKA subtype I activity. Inhibitionof overall PKA activity, or of PKA subtype II anchoring, diminishedcAMP/PKA-mediated proliferation in NC cultures but had no effect on CYcultures. Polarized CY monolayers remained proliferative, but NCmonolayers lost responsiveness. No large proliferation changes resultedfrom treatments of polarized cultures; however, polarized NC and CY cultures differed in poststimulation handling of PKA catalytic and typeII regulatory subunits. Our results support PKA subtype regulationof prepolarization proliferation in NC principal cells and alteredregulation of PKA in CY cells and suggest that differences at ordownstream of PKA can contribute to altered proliferation in adevelopmental renal disease.