Glucose enhances mesangial cell apoptosis

Khera, Tarnjit, Martin, John, Riley, Stephen George, Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496 and Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113 2006. Glucose enhances mesangial cell apoptosis. Laboratory Investigation 86 (6) , pp. 566-577. 10.1038/labinvest.3700418

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Abstract

Mesangial cell apoptosis occurs in experimental diabetic nephropathy, and this correlates with worsening albuminuria. This study examines the mechanism by which glucose modulates mesangial cell apoptosis. Apoptosis was induced in mesangial cells by serum deprivation in the presence of 5 or 25 mM D-glucose, and examined by expression of Annexin-V and disruption of mitochondrial transmembrane potential. Involvement of Bax, Bcl-2 and NF-kappaB were examined by RT-PCR and EMSA. Involvement of TGF-beta1 was sought by determining the effect of recombinant TGF-beta1on apoptosis and the mediators of the apoptotic pathway (Bcl2/Bax and NF-kappaB). Culture of cells in the presence of 25 mM D-glucose (i) enhanced apoptosis stimulated by serum depletion, (ii) enhanced activation of caspase-3, (iii) inhibited NF-kappaB activation, and (iv) decreased Bcl-2:Bax ratio. Inhibition of NF-kappaB using SN50, also increased mesangial cell apoptosis, and decreased Bcl-2:Bax ratio. Addition of TGF-beta1 to mesangial cells mimicked the effect of high glucose reducing NF-kappaB expression and Bcl-2:Bax ratio. Furthermore glucose-mediated enhanced apoptosis was inhibited by the addition of a blocking antibody to TGF-beta1. Exposure of mesangial cells to 25 mM D-glucose stimulated the generation of both total and active TGF-beta1 in the cell culture supernatant, this increase was only significant after 48-72 h, that is at a time point later than enhanced apoptosis. Addition of 25 mM D-glucose, however, increased sensitivity of mesangial cells to TGF-beta1 as assessed by luciferase activity of a Smad sensitive reporter construct. The data suggest that elevated glucose concentration enhanced the pathway leading to apoptosis following serum deprivation. Furthermore, it is likely that this is dependent on glucose-mediated enhanced sensitivity to endogenous TGF-beta1 rather than glucose stimulated de novo TGF-beta1 synthesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Uncontrolled Keywords:	apoptosis ; glucose ; diabetes ; mesangial cells ; TGF-beta
Publisher:	Nature Publishing Group
ISSN:	1530-0307
Last Modified:	01 Jul 2024 16:16
URI:	https://orca.cardiff.ac.uk/id/eprint/457

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