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Regulation of (pro)renin receptor expression by glucose-induced mitogen-activated protein kinase, nuclear

Jiqian Huang1, Helmy M Siragy

  • 1Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1409, USA.

Endocrinology
|May 7, 2010
PubMed

Insights

High glucose increases renal (pro)renin receptor (PRR) expression via protein kinase C (PKC) pathways. These pathways involve Raf-ERK and JNK-c-Jun signaling, leading to increased PRR transcription in mesangial cells.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Endocrinology

Background:

  • Renal (pro)renin receptor (PRR) expression is elevated in diabetes mellitus.
  • The precise molecular mechanisms driving this upregulation remain incompletely understood.

Purpose of the Study:

  • To investigate the signaling pathways involved in high glucose-induced upregulation of renal PRR.
  • To elucidate the roles of protein kinase C (PKC), Raf-ERK, and JNK-c-Jun pathways in regulating PRR expression.

Main Methods:

  • Rat mesangial cells were treated with high glucose (30 mm d-glucose).
  • PRR mRNA and protein expression were measured.
  • Western blotting assessed phosphorylation of key signaling proteins (Raf-1, ERK, JNK, NF-kappaB, c-Jun).
  • Chromatin immunoprecipitation and EMSA analyzed transcription factor binding to the PRR promoter.
  • Specific inhibitors were used to block signaling pathways.

Main Results:

  • High glucose significantly increased PRR mRNA and protein levels in mesangial cells.
  • Elevated glucose induced phosphorylation of Raf-1, ERK, JNK, NF-kappaB p65, and c-Jun.
  • NF-kappaB and activator protein (AP)-1 binding to the PRR promoter increased under high glucose conditions.
  • Inhibitors of PKC, Raf-1, MEK, JNK, NF-kappaB, and AP-1 attenuated high glucose-induced PRR upregulation.

Conclusions:

  • High glucose upregulates renal PRR expression through PKC-dependent activation of both Raf-ERK and JNK-c-Jun signaling pathways.
  • NF-kappaB and AP-1 transcription factors play crucial roles in mediating high glucose-induced PRR transcription in rat mesangial cells.

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