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Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells

Y Huang1, N A Noble, J Zhang

  • 1Division of Nephrology, Fibrosis Research Laboratory, University of Utah, Salt Lake City, Utah 84108, USA.

Kidney International
|March 31, 2007
PubMed

Insights

Renin directly activates mesangial cell proliferation and gene expression via receptor-mediated pathways, independent of angiotensin II. This finding reveals a novel signaling system contributing to renin

Area of Science:

  • Molecular Biology
  • Renal Physiology
  • Cell Signaling

Background:

  • Emerging evidence suggests renin possesses profibrotic properties independent of angiotensin II.
  • The precise signaling pathways mediating renin's direct profibrotic effects remain largely unknown.
  • Understanding these pathways is crucial for elucidating renin's role in fibrotic diseases.

Purpose of the Study:

  • To investigate whether renin receptor activation directly triggers the extracellular-signal regulated kinase 1 and 2 (ERK1/2) pathway in mesangial cells.
  • To determine if this renin-mediated activation is independent of the angiotensin II system.
  • To elucidate the downstream consequences of renin-induced ERK1/2 activation on gene expression and cell proliferation.

Main Methods:

  • Treatment of mesangial cells with recombinant rat renin.
  • Assessment of ERK1/2 phosphorylation using Western blotting.
  • Inhibition studies using ERK kinase inhibitors and small-inhibiting RNA (siRNA) against the renin receptor.
  • Measurement of transforming growth factor-beta1 (TGF-beta1) and plasminogen activator inhibitor-1 (PAI-1) mRNA expression.

Main Results:

  • Recombinant rat renin induced rapid, dose- and time-dependent ERK1/2 phosphorylation and mesangial cell proliferation.
  • Renin-induced ERK1/2 activation was unaffected by angiotensin-converting enzyme inhibition or angiotensin receptor blockade, indicating an angiotensin II-independent mechanism.
  • Inhibition of ERK kinase or blockade of the renin receptor via siRNA significantly attenuated renin-induced ERK1/2 activation, TGF-beta1, and PAI-1 mRNA expression.

Conclusions:

  • Renin activates the ERK1/2 pathway in mesangial cells through a receptor-mediated, angiotensin II-independent mechanism.
  • This renin-activated signaling cascade promotes cell proliferation and upregulates profibrotic genes, including TGF-beta1 and PAI-1.
  • The identified renin-receptor-ERK1/2 pathway represents a significant contributor to renin's profibrotic actions in the kidney.

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