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Nitric oxide mediates prolyl hydroxylase 3 expression in mesangial cells and in glomerulonephritis

Ahmed Aglan1,2, Sebastian Longen1, Nathalie Dehne3

  • 1Pharmazentrum Frankfurt/ZAFES, Goethe Universität, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, D 60590, Frankfurt am Main, Germany.

Journal of Molecular Medicine (Berlin, Germany)
|January 6, 2017
PubMed

Insights

Inflammation induces prolyl hydroxylase domain containing protein 3 (PHD3) in kidney cells via NF-κB and nitric oxide (NO) pathways. This PHD3 induction is crucial for inflammatory gene expression in glomerular diseases.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Renal mesangial cells play a key role in glomerular inflammatory diseases.
  • Inflammatory signaling and hypoxia-driven pathways may interact in kidney diseases.
  • Prolyl hydroxylase domain containing proteins (PHDs) regulate hypoxia-inducible factor (HIF) stability.

Purpose of the Study:

  • To investigate the crosstalk between inflammatory signaling and hypoxia-related pathways in renal mesangial cells.
  • To analyze the expression of PHD family proteins in response to inflammatory stimuli.
  • To elucidate the regulatory mechanisms of PHD3 induction and its role in inflammatory responses.

Main Methods:

  • Primary mouse mesangial cells were stimulated with various inflammatory agents (IL-1β, TNF-α, LPS, IFN-γ).
  • mRNA expression of PHD1, PHD2, and PHD3 was quantified using RT-qPCR.
  • Inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production were assessed.
  • NF-κB and HIF-1α pathways were investigated.
  • Silencing of PHD3 was performed to evaluate its downstream effects.
  • A rat model of anti-Thy-1 glomerulonephritis was used to validate findings in vivo, with and without iNOS inhibition.

Main Results:

  • Cytokine mix (IL-1β, TNF-α) significantly increased PHD3 mRNA expression in a NF-κB-dependent manner.
  • A broader inflammatory stimulus (CM+) induced both PHD3 and PHD2, with a strong induction of PHD3 linked to iNOS expression and NO production.
  • Endogenously produced NO augmented PHD3 expression via the HIF-1α pathway.
  • Silencing PHD3 reduced the expression of NF-κB-controlled inflammatory genes (ICAM-1, MIP-2, MCP-1, CXCL-10).
  • PHD3 expression was markedly induced in a rat glomerulonephritis model, and this induction was significantly reduced by iNOS inhibition.

Conclusions:

  • PHD3 expression in mesangial cells is regulated by distinct inflammatory pathways, involving NF-κB and NO/HIF-1α signaling.
  • PHD3 plays a critical role in amplifying inflammatory responses by controlling the expression of key chemokines and adhesion molecules.
  • Targeting the NO/PHD3 axis may represent a therapeutic strategy for inflammatory glomerulonephritis.
Keywords:
Mesangial cellsNitric oxideProlyl hydroxylase domain containing protein 3

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