title: Activation of PPAR-γ inhibits PDGF-induced proliferation of mouse renal fibroblasts.
abstract: Recent studies have shown that activation of peroxisome proliferators activated receptor-γ (PPAR-γ) ameliorates renal interstitial fibrosis (RIF) in animal model. Yet, the underlying molecular mechanisms remain still largely unknown. Here, we investigated the hypothesis that activation of PPAR-γ regulates renal remodeling by modulating proliferation of primary cultured renal fibroblasts. In our present study, platelet-derived growth factor-AA (PDGF-AA), a key isoform of PDGF superfamily as mitogen in RIF, was applied to stimulate renal fibroblasts, the selective inhibitor or sequence specific siRNA of PI3K, skp2 or PPAR-γ was used to investigate the involvement of above molecular mediators in PDGF-AA-induced cell proliferation. Our results demonstrate that PDGF-AA induced proliferation of renal fibroblasts by activating PI3K/AKT signaling and resultant skp2 production. Pre-stimulation of cells with rosiglitazone or adenovirus carrying PPAR-γ cDNA (AdPPAR-γ) blocked PDGF-AA-stimulated cell proliferation, this effect was particularly coupled to PPAR-γ inhibition of AKT phosphorylation and skp2 expression. Inhibition of PPAR-γ by GW9662 restored the suppression of activated PPAR-γ on phosphorylation of AKT and subsequent skp2 production. Our results indicate that activation of PI3K/AKT signaling and resultant skp2 generation mediated PDGF-induced proliferation of renal fibroblasts. Activation of PPAR-γ inhibited cell proliferation by inhibition of AKT phosphorylation and its down-streams.
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 277, West of Yanta Road, Xi'an 710061, Shaanxi, PR China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Baosong
authors.initials: B
authors.lastname: Gui
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Ganglian
authors.initials: G
authors.lastname: Yao
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Ge
authors.affiliation: Department of Nephrology Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an 710004, Shaanxi, PR China. Electronic address: rgf2015@sohu.com.
authors.forename: Rongguo
authors.initials: R
authors.lastname: Fu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D024042:Collagen Type I; D047495:PPAR gamma; D010982:Platelet-Derived Growth Factor; D044786:S-Phase Kinase-Associated Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Peroxisome proliferators activated receptor-γ (PPAR-γ); Platelet-derived growth factor (PDGF); Proliferation; S-phase kinase associated protein-2 (Skp2)