Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase

S. Shastry, A. J. Ingram, J. W. Scholey, L. R. James

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Hyperhomocysteinemia is prevalent among patients with chronic kidney disease (CKD) and has been linked to progressive kidney and vascular diseases. Increased glomerular mesangial cell (MC) turnover, including proliferation and apoptosis, is a hallmark of CKD. Activation of p38-mitogen-activated protein kinase (p38-MAPK) has been linked to apoptosis in many cell lines. Accordingly, we studied the effect of homocysteine (Hcy) on MC p38-MAPK signalling and apoptosis. Hcy (50 μM/24 h) increased MC apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) and single-stranded DNA (ssDNA) analysis. In addition to increases in pro-caspase-3 protein and caspase-3 activity, cells exposed to Hcy manifested enhanced reactive oxygen species content. Hcy increased p38-MAPK activity (fivefold), with maximal effect at 50 μM and 20 min; p38-MAPK activation was attenuated by N-acetylcysteine (Nac) and catalase (Cat), further indicating that the effect was via oxidative stress. Confocal microscopy revealed activation and nuclear translocation of p38-MAPK that was attenuated by Cat. In addition, Hcy-induced apoptosis as determined by TUNEL and ssDNA assay was abrogated by Nac, Cat, and SB203580 (p38-MAPK inhibitor). We conclude that in MC, Hcy (i) activates p38-MAPK and increases p38MAPK nuclear translocation via an oxidative stress dependent mechanism and (ii) induces DNA damage and apoptosis that is dependent on oxidative stress and p38-MAPK activation.

Original languageEnglish (US)
Pages (from-to)304-311
Number of pages8
JournalKidney International
Volume71
Issue number4
DOIs
StatePublished - Feb 1 2007

Fingerprint

Mesangial Cells
Homocysteine
p38 Mitogen-Activated Protein Kinases
Apoptosis
Catalase
Oxidative Stress
Single-Stranded DNA
In Situ Nick-End Labeling
Acetylcysteine
Chronic Renal Insufficiency
Caspase 3
Hyperhomocysteinemia
DNA Nucleotidylexotransferase
Kidney Diseases
Protein Kinase Inhibitors
Vascular Diseases
Confocal Microscopy
DNA Damage
Reactive Oxygen Species
Cell Line

Keywords

  • Apoptosis
  • Mesangial cells
  • Oxidative stress
  • Signalling
  • p38-MAPK

ASJC Scopus subject areas

  • Nephrology

Cite this

Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase. / Shastry, S.; Ingram, A. J.; Scholey, J. W.; James, L. R.

In: Kidney International, Vol. 71, No. 4, 01.02.2007, p. 304-311.

Research output: Contribution to journalArticle

Shastry, S. ; Ingram, A. J. ; Scholey, J. W. ; James, L. R. / Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase. In: Kidney International. 2007 ; Vol. 71, No. 4. pp. 304-311.
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