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STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia-reperfusion injury.
Kemmner, Stephan; Bachmann, Quirin; Steiger, Stefanie; Lorenz, Georg; Honarpisheh, Mohsen; Foresto-Neto, Orestes; Wang, Shijun; Carbajo-Lozoya, Javier; Alt, Verena; Schulte, Christian; Chmielewski, Stefan; Bluyssen, Hans A R; Heemann, Uwe; Baumann, Marcus; Lech, Maciej; Schmaderer, Christoph.
Afiliación
  • Kemmner S; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Bachmann Q; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Steiger S; Medizinische Klinik und Poliklinik IV, Department of Nephrology, Klinikum der Ludwig-Maximilians-Universität München, Munich , Germany.
  • Lorenz G; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Honarpisheh M; Medizinische Klinik und Poliklinik IV, Department of Nephrology, Klinikum der Ludwig-Maximilians-Universität München, Munich , Germany.
  • Foresto-Neto O; Medizinische Klinik und Poliklinik IV, Department of Nephrology, Klinikum der Ludwig-Maximilians-Universität München, Munich , Germany.
  • Wang S; Pediatric Research Center, Hannover Medical School , Hannover , Germany.
  • Carbajo-Lozoya J; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Alt V; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Schulte C; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Chmielewski S; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Bluyssen HAR; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan , Poznan , Poland.
  • Heemann U; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan , Poznan , Poland.
  • Baumann M; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Lech M; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich , Munich , Germany.
  • Schmaderer C; Medizinische Klinik und Poliklinik IV, Department of Nephrology, Klinikum der Ludwig-Maximilians-Universität München, Munich , Germany.
Am J Physiol Renal Physiol ; 316(2): F277-F291, 2019 02 01.
Article en En | MEDLINE | ID: mdl-30403164
ABSTRACT
Renal ischemia-reperfusion injury (IRI) leads to acute kidney injury or delayed allograft function, which predisposes to fibrosis in the native kidney or kidney transplant. Here we investigated the role of the signal transducer and activator of transcription 1 (STAT1) in inflammatory responses following renal IRI. Our study showed that a subsequent stimulation of Janus-activated kinase 2/STAT1 and Toll-like receptor 4 pathways led to greater STAT1 activation followed by increased cytokine transcription compared with single-pathway stimulation in murine renal tubular cells. Moreover, we observed increased activation of STAT1 under hypoxic conditions. In vivo, STAT1-/- mice displayed less acute tubular necrosis and decreased macrophage infiltration 24 h after renal ischemia. However, investigation of the healing phase (30 days after IRI) revealed significantly more fibrosis in STAT1-/- than in wild-type kidneys. In addition, we demonstrated increased macrophage infiltration in STAT1-/- kidneys. Flow cytometry analysis revealed that STAT1 deficiency drives an alternatively activated macrophage phenotype, which is associated with downregulated cluster of differentiation 80 expression, decreased intracellular reactive oxygen species production, and enhanced ability for phagocytosis. Furthermore, we detected immunohistochemically enhanced STAT1 expression in human renal allograft biopsies with no interstitial fibrosis/tubular atrophy (IF/TA) compared with specimens with severe IF/TA without specific etiology. Thus, STAT1 activation drives macrophages toward an alternatively activated phenotype and enhances fibrogenesis indicating a potential STAT1-driven protective mechanism in tissue repair after ischemic injury.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Daño por Reperfusión / Células Epiteliales / Factor de Transcripción STAT1 / Enfermedades Renales / Túbulos Renales / Activación de Macrófagos / Macrófagos Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Am J Physiol Renal Physiol Asunto de la revista: FISIOLOGIA / NEFROLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Daño por Reperfusión / Células Epiteliales / Factor de Transcripción STAT1 / Enfermedades Renales / Túbulos Renales / Activación de Macrófagos / Macrófagos Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Am J Physiol Renal Physiol Asunto de la revista: FISIOLOGIA / NEFROLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Alemania