title: Relevant role of PKG in the progression of fibrosis induced by TNF-like weak inducer of apoptosis.
abstract: TNF-like weak inducer of apoptosis (TWEAK) is an inflammatory cytokine that activates the FGF-inducible 14 receptor. Both TWEAK and the FGF-inducible 14 receptor are constitutively expressed in the kidney. TWEAK has been shown to modulate several biological responses, such as inflammation, proliferation, differentiation, and apoptosis, that contribute to kidney injury. However, the role of TWEAK in fibrosis and TWEAK-activated intracellular signaling pathways remain poorly understood. We tested the hypothesis that TWEAK can be a potent inducer of renal fibrosis by increasing transforming growth factor (TGF)-β1 expression (a well-known switch in the fibrosis process) through PKG-I downregulation. We showed that in human mesangial cells, TWEAK increased TGF-β1 expression and activity, leading to higher levels of the extracellular matrix protein fibronectin and decreased PKG-I expression and activity via the Ras pathway. PKG-I activation with 8-bromo-cGMP, Ras inactivation with dominant negative Ras, or Ras pathway inhibition with the ERK1/2 inhibitor PD-98059 resulted in the prevention of TWEAK-induced TGF-β1 upregulation. In vivo, exogenous administration of TWEAK to wild-type mice downregulated kidney PKG-I and increased kidney TGF-β1 expression. These effects were blunted in H-Ras knockout mice. Together, these data demonstrate, for the first time, the key role of PKG-I in TGF-β1 induction by TWEAK in kidney cells.
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín
authors.affiliation: REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: Inés
authors.initials: I
authors.lastname: Mora
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: M Alicia
authors.initials: MA
authors.lastname: Cortes
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: Andrea
authors.initials: A
authors.lastname: García-Jerez
authors.affiliation: REDinREN (Instituto de Salud Carlos III), Madrid, Spain; IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
authors.affiliation: REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain; Department of Medicine, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; Nephrology Section and Research Unit, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; and.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
authors.affiliation: Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain; REDinREN (Instituto de Salud Carlos III), Madrid, Spain; Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain; gemma.olmos@uah.es.
authors.forename: Gemma
authors.initials: G
authors.lastname: Olmos
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569720:Prkg1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Ras protein; fibrosis; kidney; protein kinase G-I; transforming growth factor-β1; tumor necrosis factor-like weak inducer of apoptosis