STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia-reperfusion injury

Stephan Kemmner, Quirin Bachmann, Stefanie Steiger, Georg Lorenz, Mohsen Honarpisheh, Orestes Foresto-Neto, Shijun Wang, Javier Carbajo-Lozoya, Verena Alt, Christian Schulte, Stefan Chmielewski, Hans A.R. Bluyssen, Uwe Heemann, Marcus Baumann, Maciej Lech, Christoph Schmaderer

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)F277-F291
JournalAmerican Journal of Physiology - Renal Physiology
Volume316
Issue number2
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Acute kidney injury
  • Interstitial fibrosis and tubular atrophy
  • Renal fibrosis
  • Renal ischemia-reperfusion injury
  • STAT1

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