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TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.
Cordido, Adrian; Nuñez-Gonzalez, Laura; Martinez-Moreno, Julio M; Lamas-Gonzalez, Olaya; Rodriguez-Osorio, Laura; Perez-Gomez, Maria Vanessa; Martin-Sanchez, Diego; Outeda, Patricia; Chiaravalli, Marco; Watnick, Terry; Boletta, Alessandra; Diaz, Candido; Carracedo, Angel; Sanz, Ana B; Ortiz, Alberto; Garcia-Gonzalez, Miguel A.
Afiliación
  • Cordido A; Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain.
  • Nuñez-Gonzalez L; Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain.
  • Martinez-Moreno JM; RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain.
  • Lamas-Gonzalez O; Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain.
  • Rodriguez-Osorio L; Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain.
  • Perez-Gomez MV; Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain.
  • Martin-Sanchez D; Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain.
  • Outeda P; RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain.
  • Chiaravalli M; Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain.
  • Watnick T; RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain.
  • Boletta A; Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain.
  • Diaz C; RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain.
  • Carracedo A; Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain.
  • Sanz AB; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • Ortiz A; Division of Genetics and Cell Biology, Molecular Basis of Cystic Kidney Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)-San Raffaele Scientific Institute, Milan, Italy.
  • Garcia-Gonzalez MA; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
J Am Soc Nephrol ; 32(8): 1913-1932, 2021 08.
Article en En | MEDLINE | ID: mdl-34155062
BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Riñón Poliquístico Autosómico Dominante / Citocina TWEAK / Receptor de TWEAK Tipo de estudio: Prognostic_studies / Systematic_reviews Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Riñón Poliquístico Autosómico Dominante / Citocina TWEAK / Receptor de TWEAK Tipo de estudio: Prognostic_studies / Systematic_reviews Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos