title: Parathyroid hormone-related protein is a mitogenic and a survival factor of mesangial cells from male mice: role of intracrine and paracrine pathways.
abstract: Glomerulonephritis is characterized by the proliferation and apoptosis of mesangial cells (MC). The parathyroid-hormone related protein (PTHrP) is a locally active cytokine that affects these phenomena in many cell types, through either paracrine or intracrine pathways. The aim of this study was to evaluate the effect of both PTHrP pathways on MC proliferation and apoptosis. In vitro studies were based on MC from male transgenic mice allowing PTHrP-gene excision by a CreLoxP system. MC were also transfected with different PTHrP constructs: wild type PTHrP, PTHrP devoid of its signal peptide, or of its nuclear localization sequence. The results showed that PTHrP deletion in MC reduced their proliferation even in the presence of serum and increased their apoptosis when serum-deprived. PTH1R activation by PTHrP(1-36) or PTH(1-34) had no effect on proliferation but improved MC survival. Transfection of MC with PTHrP devoid of its signal peptide significantly increased their proliferation and minimally reduced their apoptosis. Overexpression of PTHrP devoid of its nuclear localization sequence protected cells from apoptosis without changing their proliferation. Wild type PTHrP transfection conferred both mitogenic and survival effects, which seem independent of midregion and C-terminal PTHrP fragments. PTHrP-induced MC proliferation was associated with p27(Kip1) down-regulation and c-Myc/E2F1 up-regulation. PTHrP increased MC survival through the activation of cAMP/protein kinase A and PI3-K/Akt pathways. These results reveal that PTHrP is a cytokine of multiple roles in MC, acting as a mitogenic factor only through an intracrine pathway, and reducing apoptosis mainly through the paracrine pathway. Thus, PTHrP appears as a probable actor in MC injuries.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U682, Equipe Cancer du Rein et Physiopathologie Rénale, Faculté de Médecine, 11 rue Humann, F-67085 Strasbourg, France. alicante81@yahoo.com
authors.forename: Mazène
authors.initials: M
authors.lastname: Hochane
authors.forename: Denis
authors.initials: D
authors.lastname: Raison
authors.forename: Catherine
authors.initials: C
authors.lastname: Coquard
authors.forename: Olivier
authors.initials: O
authors.lastname: Imhoff
authors.forename: Thierry
authors.initials: T
authors.lastname: Massfelder
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulin
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Helwig
authors.forename: Mariette
authors.initials: M
authors.lastname: Barthelmebs
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000502:physiology; D005921:Glomerulonephritis / Q000503:physiopathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D014162:Transfection
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D008934:Mitogens; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27