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Reactive oxygen species and nuclear factor-kappa B pathway mediate high glucose-induced Pax-2 gene expression in

Y-W Chen1, F Liu, S Tran

  • 1Université Montréal, Centre hospitalier de l'Université de Montréal (CHUM)-Hôtel-Dieu, Pavillon Masson, Montréal, Québec, Canada.

Kidney International
|September 21, 2006
PubMed

Insights

High glucose levels in diabetes mellitus can harm developing kidneys by increasing the expression of the essential gene Pax-2 (paired box-2). This occurs through reactive oxygen species and NF-kappa B signaling.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Endocrinology

Background:

  • Diabetes mellitus is a significant risk factor for congenital malformations, particularly affecting kidney development (diabetic embryopathy).
  • The paired box-2 (Pax-2) gene plays a critical role in the development of the kidney (nephrogenesis).

Purpose of the Study:

  • To investigate the impact of high glucose on Pax-2 gene expression in kidney development.
  • To elucidate the molecular mechanisms underlying high glucose-induced alterations in Pax-2 expression.

Main Methods:

  • Utilized in vitro (mouse embryonic mesenchymal epithelial cells - MK4) and ex vivo (Hoxb7-GFP mouse kidney explants) models.
  • Assessed Pax-2 gene expression via RT-PCR, Western blotting, and immunofluorescence.
  • Investigated signaling pathways including NF-kappa B, ROS generation, PKC, p38 MAPK, and p44/42 MAPK using reporter gene assays and specific inhibitors.

Main Results:

  • High glucose (25 mM) significantly induced Pax-2 gene expression in both MK4 cells and kidney explants compared to normal glucose (5 mM).
  • High glucose-induced Pax-2 expression was mediated by reactive oxygen species (ROS) generation and activation of the nuclear factor kappa B (NF-kappa B) signaling pathway.
  • Signaling pathways including protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK were not found to be involved.

Conclusions:

  • High glucose conditions, mimicking diabetes, can disrupt normal kidney development by upregulating Pax-2 expression.
  • The findings highlight ROS generation and NF-kappa B activation as key mechanisms linking hyperglycemia to altered Pax-2 expression during embryogenesis.

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