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Differential contribution of three mitogen-activated protein kinases to PDGF-BB-induced mesangial cell proliferation

Hitomi Kawano1, Shokei Kim, Kensuke Ohta

  • 1Department of Pharmacology, Osaka City University Medical School, Japan.

Journal of the American Society of Nephrology : JASN
|February 22, 2003
PubMed

Insights

Mitogen-activated protein (MAP) kinases, specifically ERK and JNK, drive human mesangial cell proliferation and gene expression in response to PDGF-BB. These pathways are implicated in glomerular disease progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Renal Pathophysiology

Background:

  • Platelet-derived growth factor-BB (PDGF-BB) is a key mediator in glomerular diseases.
  • Mitogen-activated protein (MAP) kinases, including ERK, JNK, and p38, are critical signaling molecules in cellular processes.
  • Understanding the specific roles of MAP kinases in PDGF-BB-induced mesangial cell (MC) responses is crucial for elucidating disease mechanisms.

Purpose of the Study:

  • To investigate the involvement of specific MAP kinases (ERK, JNK, p38) in PDGF-BB-induced proliferation of human mesangial cells (MC).
  • To determine the role of these MAP kinases in regulating the expression of key genes (TGF-beta1, MCP-1, PAI-1) stimulated by PDGF-BB.
  • To elucidate the contribution of MAP kinases to activator protein-1 (AP-1) activation in response to PDGF-BB.

Main Methods:

  • Human mesangial cells (MC) were treated with PDGF-BB.
  • Recombinant adenoviruses encoding dominant-negative mutants of ERK, JNK, p38, and c-Jun were used to inhibit specific signaling pathways.
  • Cell proliferation was assessed by [(3)H]thymidine incorporation and cell counting.
  • Gene expression (TGF-beta1, MCP-1, PAI-1) was analyzed using mRNA analysis.
  • AP-1 activation was measured to assess pathway involvement.

Main Results:

  • Both ERK and JNK, but not p38, were essential for PDGF-BB-induced MC proliferation.
  • ERK mediated the expression of MCP-1 and PAI-1, while JNK and p38 regulated TGF-beta1 and MCP-1 expression.
  • JNK and p38, but not ERK, were involved in PDGF-BB-induced AP-1 activation, which was critical for proliferation and gene expression.

Conclusions:

  • ERK and JNK play distinct and crucial roles in PDGF-BB-induced human mesangial cell proliferation.
  • Different MAP kinases differentially regulate the expression of TGF-beta1, MCP-1, and PAI-1, highlighting pathway specificity.
  • The findings suggest that targeting specific MAP kinase pathways could offer therapeutic strategies for glomerular diseases.

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