Role of oxidative stress in advanced glycation end product-induced mesangial cell activation
2002 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 61, no 6, 2006-2014 p.Article in journal (Refereed) Published
Background. Levels of advanced glycation end products (AGE) are elevated in individuals with advancing age, renal failure, and diabetes, and accumulation of these molecules may contribute to disease progression. The mechanism by which AGE proteins alter glomerular mesangial cell function, however, is not completely understood. The present study assessed the involvement of oxidative stress in AGE-dependent mesangial cell signaling events. Methods. Primary cultures of rat renal mesangial cells were exposed to in vitro AGE-BSA and H-2 O-2 . Nuclear factor-kappaB (NF-kappaB) and protein kinase C (PKC) isoform activation were studied using confocal microscopy and Western blotting. Quantitative polymerase chain reaction (PCR) was used to measure transforming growth factor-beta1 (TGF-beta1) levels. The involvement of oxidative stress was assessed by supplementing or compromising cellular antioxidant capacity. Results. NF-kappaB was dose-dependently activated by AGE. PKC activation was not involved in this response, but analysis of PKC-beta1 activation showed a stimulatory effect of AGE proteins on this isoform. Transcription of TGF-beta1 was stimulated by AGE and was prevented by PKC inhibition. Challenge with H-2 O-2 had similar downstream effects on mesangial cell signaling. Antioxidants, vitamin E and nitecapone, prevented AGE-dependent NF-kappaB activation and normalized PKC activity and associated TGF-beta1 transcription. Depletion of the intracellular antioxidant, glutathione, effectively lowered the AGE concentration needed for mesangial cell activation of NF-kappaB and PKC-beta1. Treatment with a suboptimal AGE dose, under glutathione-depleted conditions, revealed a synergistic effect on both parameters. Conclusion. The results support a central role for oxidative stress in AGE-dependent mesangial cell signaling and emphasize the importance of ROS in determining cell responsiveness.
Place, publisher, year, edition, pages
2002. Vol. 61, no 6, 2006-2014 p.
AGE, diabetes, oxidative stress, NF-kappa B, protein kinase C, TGF-beta 1, d-alpha-tocopherol, diabetic rats, endothelial-cells, gene-expression, oxidant stress, growth-factor, antioxidant, complications, glycosylation, proteins
IdentifiersURN: urn:nbn:se:kth:diva-21554ISI: 000175666100009OAI: oai:DiVA.org:kth-21554DiVA: diva2:340252
QC 201005252010-08-102010-08-10Bibliographically approved