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Ras Activation Modulates Methylglyoxal-Induced Mesangial Cell Apoptosis Through Superoxide Production.
- Source :
-
Renal Failure . 2007, Vol. 29 Issue 7, p911-921. 11p. 7 Graphs. - Publication Year :
- 2007
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *KIDNEY diseases
*GLUCOSE
*APOPTOSIS
*SUPEROXIDE dismutase
*CELLS
Subjects
Details
- Language :
- English
- ISSN :
- 0886022X
- Volume :
- 29
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Renal Failure
- Publication Type :
- Academic Journal
- Accession number :
- 27442328
- Full Text :
- https://doi.org/10.1080/08860220701573509