Ras activation modulates methylglyoxal-induced mesangial cell apoptosis through superoxide production

Wei Jan Huang, Chun Wu Tung, Cheng Ho, Jen Tsung Yang, Min Li Chen, Pey Jium Chang, Pei Hsien Lee, Chun Liang Lin, Jeng Yi Wang

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Aims. While previous studies have demonstrated that diabetic nephropathy is attributable to glucose-derived dicarbonyl compounds, methylglyoxal (MGO)-inducing apoptosis in renal mesangial cells, the molecular mechanism of upper stream redox signaling modulation, has not been fully elucidated. Methods: Rat mesangial cells pretreated with or without superoxide dismutase, diphenyloniodium, SB203580, and manumycin A were cultured in methylglyoxal stress-induced apoptosis. Signaling protein expression, flow cytometry, and morphological features of apoptotic cell death were assessed. Results: Methylglyoxal decreased cell viability in mesangial cells. Superoxide mediated methylglyoxal-induced caspase 3 cleavage. Pretreatment with diphenyloniodium, SB203580, and manumycin A reduced methylglyoxal augmentation of superoxide synthesis and caspase-3 activation. Methylglyoxal rapidly enhanced Ras activation and progressively increased cytosolic P38 and nuclear c-Jun activation. Scavenging of superoxide by superoxide dismutase or diphenyloniodium, inhibiting P38 by SB203580, and inhibiting Ras with manumycin A successfully reduced the promoting effect of methylglyoxal on P38 and c-Jun phosphorylation (activation). Furthermore, pretreatment with superoxide dismutase, diphenyloniodium, SB203580, and manumycin A significantly attenuated methylglyoxal induction of apoptosis on the basis of Annexin-V assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labelling (TUNEL) staining. Conclusions. This study has shown that methylglyoxal increased Ras modulation of superoxide-mediated P38 activation and c-Jun activation, which resulted in increased apoptosis.

Original languageEnglish
Pages (from-to)911-921
Number of pages11
JournalRenal Failure
Volume29
Issue number7
DOIs
Publication statusPublished - Sep 2007
Externally publishedYes

Keywords

  • Apoptosis
  • Diabetes
  • Ras
  • Renal mesangial cells
  • Superoxide

ASJC Scopus subject areas

  • Nephrology

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    Huang, W. J., Tung, C. W., Ho, C., Yang, J. T., Chen, M. L., Chang, P. J., Lee, P. H., Lin, C. L., & Wang, J. Y. (2007). Ras activation modulates methylglyoxal-induced mesangial cell apoptosis through superoxide production. Renal Failure, 29(7), 911-921. https://doi.org/10.1080/08860220701573509