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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Extracellular regulated protein kinases play a key role via bone morphogenetic protein 4 in high phosphate-induced

Ling Qin1, Bo Tang1, Bingqing Deng1

  • 1Department of Nephrology & Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Life Sciences
|April 22, 2015
PubMed
Abstract

Insights

In chronic kidney disease, high phosphate induces endothelial cell apoptosis. Inhibiting ERK MAPK upregulates bone morphogenetic protein 4 (BMP4), protecting cells from hyperphosphatemia-induced damage.

Area of Science:

  • Cardiovascular biology
  • Endothelial cell function
  • Molecular mechanisms of kidney disease

Background:

  • Hyperphosphatemia is a significant risk factor for cardiovascular events in chronic kidney disease patients.
  • High phosphate levels are known to induce endothelial cell apoptosis, but the underlying mechanisms require elucidation.
  • Understanding these mechanisms is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms by which high phosphate induces apoptosis in human umbilical vein endothelial cells (HUVECs).
  • To identify key genes and pathways involved in hyperphosphatemia-induced endothelial cell apoptosis.
  • To explore potential therapeutic targets for mitigating cardiovascular risks associated with chronic kidney disease.

Main Methods:

  • Microarray analysis of HUVECs cultured in high (3.0mM) versus normal (1.0mM) phosphate conditions.
  • Bioinformatic analysis to identify differentially expressed genes and key signaling pathways, including MAPK.
  • Validation of microarray findings using Annexin V/PI staining, caspase-3 cleavage assays, immunoblotting, and quantitative real-time PCR.
  • Assessment of the role of bone morphogenetic protein 4 (BMP4) and extracellular signal-regulated kinases (ERKs) in high phosphate-induced apoptosis.

Main Results:

  • Microarray analysis identified the mitogen-activated protein kinase (MAPK) pathway as critical.
  • Gene coexpression network analysis suggested bone morphogenetic protein 4 (BMP4) as a key regulatory gene, with its expression decreased under high phosphate conditions.
  • Extracellular regulated protein kinases (ERKs) were activated; however, inhibiting ERK with U0126 increased BMP4 expression and reduced endothelial cell apoptosis.
  • Pretreatment with BMP4 protein also reduced apoptosis, but did not affect ERK MAPK activation, suggesting a parallel protective pathway.

Conclusions:

  • Inhibition of the ERK MAPK pathway protects endothelial cells from hyperphosphatemia-induced apoptosis by upregulating BMP4.
  • This study identifies a novel mechanism linking high phosphate, ERK MAPK, BMP4, and endothelial cell apoptosis.
  • The findings provide potential molecular targets for novel therapeutic strategies to reduce endothelial cell apoptosis and cardiovascular events in chronic kidney disease.
Keywords:
ApoptosisBone morphogenetic protein 4Endothelial cellsExtracellular regulated protein kinasesHyperphosphatemia

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