title: Parathyroid hormone-mitogen-activated protein kinase axis exerts fibrogenic effect of connective tissue growth factor on human renal proximal tubular cells.
abstract: BACKGROUND
  Enhanced and prolonged expression of connective tissue growth factor (CTGF) is associated with kidney fibrosis. Parathyroid hormone (PTH) is involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa in renal failure. PTH activated mitogen-activated protein kinase (MAPK) signaling pathway is present in renal tubular cells. The aim of this study was to identify the mechanism how the signal is transduced to result in extracellular signal-regulated protein kinase (ERK) activation, leading to upregulation of CTGF.
  
  
  METHODS
  The levels of CTGF mRNA and protein in human kidney proximal tubular cells (HK-2) treated with PTH in the presence or absence of the MAPK inhibitor PD98059 were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) and immunoblotting assay. The activation of the CTGF promoter in HK-2 cells was determined by the dual-luciferase assay. The effects of the protein kinase A (PKA) activator 8-Br-cAMP and protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on MAPK phosphorylation, and the effects of the PKA inhibitor H89 and PKC inhibitor calphostin C on MAPK phosphorylation and CTGF expression were detected by immunoblotting assay.
  
  
  RESULTS
  PD98059 inhibited the PTH stimulated expression of CTGF, which strongly suggested that the MAPK signaling pathway plays an important role in the PTH-induced CTGF upregulation in renal tubular cells. A PKA activator as well as PKC activators induced MAPK phosphorylation, and both PKA and PKC inhibitors antagonized PTH-induced MAPK phosphorylation and CTGF expression.
  
  
  CONCLUSIONS
  CTGF expression is upregulated by PTH through a PKC/PKA-ERK-dependent pathway.
authors.affiliation: Department of Nephrology, General Hospital of Jinan Military Command, Jinan, Shandong 250031, China.
authors.forename: Yun-Shan
authors.initials: YS
authors.lastname: Guo
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Yuan
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Zhang
authors.forename: Yao-Hai
authors.initials: YH
authors.lastname: Ding
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
mesh_terms: D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology
chemical_list: D005419:Flavonoids; D010281:Parathyroid Hormone; D055513:Connective Tissue Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one