title: The absence of prostaglandin e1 returned confluent cultures of highly proliferative murine polycystic kidney principal cells to a normal proliferation level.
abstract: Constitutively high proliferation, loss of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)-regulated proliferation, and half-normal cAMP levels were observed previously in principal cells from the C57BL/6J- Cyc1\[cf12\]cpk\[cf1\] (cpk) model of autosomal recessive polycystic kidneys disease (PKD) cultured in defined medium supplemented with prostaglandin E1 (PGE1). Because PGE1 can up- or down-regulate renal cAMP production depending upon its receptor coupling; cAMP exerted both PKA-dependent and PKA-independent effects on cell proliferation; proliferation is considered to be a component of cystogenesis; and PGE1 resulted in loss of tubular structures and formation of cystic structures in gel culture of Madin Darby Canine Kidney cells; the effect of removing PGE1 on murine principal cell proliferation was examined. Proliferation was measured in filter-grown cultures of cystic (cpk) and noncystic (C57) principal cells from cpk and C57BL/6J mice, respectively. Lack of PGE1 had no effect on subconfluent C57 and cpk cultures or confluent C57 cultures but had a dramatic effect on confluent cpk cultures. Without PGE1, cpk proliferation was comparable with the low C57 level. In PGE1-deficient medium, differences were observed between confluence conditions and cell types for responses to a cAMP analog and a PKA activity inhibitor that suggested altered regulation of both PKA-dependent and PKA-independent cell proliferation. Cyclic adenosine monophosphate-dependent differences reported here, and previously, support the idea that the combination of mutant PKD gene product, altered PGE1 responsiveness, and altered PKA targeting contributes to activation of a cystogenic signaling pathway that regulates principal cell proliferation and is involved in pathogenesis.
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine Cleveland, Ohio 44106-6003, USA. sao3@po.cwru.edu
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Orellana
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Quinones
mesh_terms: D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D003470:Culture Media; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000527:Alprostadil