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Absence of K-Ras Reduces Proliferation and Migration But Increases Extracellular Matrix Synthesis in Fibroblasts

José M Muñoz-Félix1,2, Isabel Fuentes-Calvo1,2, Cristina Cuesta1,2

  • 1Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Instituto "Reina Sofía" de Investigación Nefrológica, Universidad de Salamanca, Salamanca, Spain.

Journal of Cellular Physiology
|February 14, 2016
PubMed

Insights

K-Ras plays a distinct role in regulating kidney fibrosis development by influencing cell proliferation, migration, and extracellular matrix production. Its absence impacts key signaling pathways, suggesting K-Ras as a potential therapeutic target.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Renal Pathophysiology

Background:

  • Ras-GTPases, including H-, N-, and K-Ras isoforms, are implicated in renal fibrosis.
  • Previous studies established roles for H- and N-Ras in fibrosis regulation.
  • The specific contribution of K-Ras to fibrosis-related cellular processes remained to be elucidated.

Purpose of the Study:

  • To investigate the role of K-Ras in fibroblast proliferation, migration, and extracellular matrix (ECM) synthesis.
  • To determine the downstream signaling pathways affected by K-Ras absence in the context of fibrosis.
  • To elucidate K-Ras's involvement in transforming growth factor-β1 (TGF-β1)-mediated fibrotic processes.

Main Methods:

  • Utilized K-Ras knockout (K-ras(-/-)) mouse embryonic fibroblasts (MEFs) and wild-type MEFs.
  • Stimulated fibroblasts with transforming growth factor-β1 (TGF-β1).
  • Assessed cell proliferation, migration, and ECM production.
  • Analyzed Ras activation, ERK and AKT phosphorylation, and Smad signaling.
  • Employed MEK inhibitor (U0126) and PI3K-AKT inhibitor (LY294002).

Main Results:

  • K-Ras knockout fibroblasts showed reduced proliferation and migration compared to wild-type.
  • Absence of K-Ras led to increased ECM production under basal conditions.
  • K-Ras deficiency resulted in decreased Ras activation and ERK phosphorylation, with increased AKT phosphorylation.
  • TGF-β1-induced Smad signaling was not affected by K-Ras absence.
  • MEK inhibition affected proliferation universally, but migration and ECM production only in wild-type cells.
  • PI3K-AKT inhibition impacted proliferation, migration, and ECM synthesis in both cell types.

Conclusions:

  • K-Ras and its downstream effectors distinctly regulate key cellular processes in fibrosis development.
  • K-Ras signaling pathways, particularly PI3K-AKT, are crucial for proliferation, migration, and ECM synthesis in fibrotic processes.
  • K-Ras may act as a significant mediator of TGF-β1 effects in renal cells, highlighting its potential as a therapeutic target.

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