Role of activator protein-1 on the effect of arginine-glycine-aspartic acid containing peptides on transforming growth factor-beta1 promoter activity.

While arginine-glycine-aspartic acid-based peptidomimetics have been employed for the treatment of cardiovascular disorders and cancer, their use in other contexts remains to be explored. Arginine-glycine-aspartic acid-serine induces Transforming growth factor-beta1 transcription in human mesangial cells, but the molecular mechanisms involved have not been studied extensively. We explored whether this effect could be due to Activator protein-1 activation and studied the potential pathways involved. Addition of arginine-glycine-aspartic acid-serine promoted Activator protein-1 binding to its cognate sequence within the Transforming growth factor-beta1 promoter as well as c-jun and c-fos protein abundance. Moreover, this effect was suppressed by curcumin, a c-Jun N terminal kinase inhibitor, and was absent when the Activator protein-1 cis-regulatory element was deleted. Activator protein-1 binding was dependent on the activity of integrin linked kinase, as transfection with a dominant negative mutant suppressed both Activator protein-1 binding and c-jun and c-fos protein increment. Integrin linked kinase was, in turn, dependent on Phosphoinositol-3 kinase activity. Arginine-glycine-aspartic acid-serine stimulated Phosphoinositol-3 kinase activity, and Transforming growth factor-beta1 promoter activation was abrogated by the use of Phosphoinositol-3 kinase specific inhibitors. In summary, we propose that arginine-glycine-aspartic acid-serine activates Integrin linked kinase via the Phosphoinositol-3 kinase pathway and this leads to activation of c-jun and c-fos and increased Activator protein-1 binding and Transforming growth factor-beta1 promoter activity. These data may contribute to understand the molecular mechanisms involved in the cellular actions of arginine-glycine-aspartic acid-related peptides and enhance their relevance as these products evolve into clinical therapeutic use.

[Renal aging]. / Envejecimiento renal.

Frequently underestimated, the deterioration of the renal function characteristic of the aging has very prominent clinical consequences. In the present article some aspects of the cellular and molecular biology of this process are analysed. The critical role of the oxidative stress and of TGFbeta are underlined. Determinant genetic factors are also mentioned. Such a knowledge can contribute to develop therapeutical strategies to prevent the decline of the.renal function that happens with the aging.

Envejecimiento renal / Renal aging

Frecuentemente infraestimado, el deterioro de la función renal característico delenvejecimiento tiene consecuencias clínicas muy relevantes. En el presente artículose analizan algunos aspectos de la biología celular y molecular de este proceso,subrayándose el papel crítico del stress oxidativo y del TGF ��, así como tambiénprobablemente de condicionantes genéticos. Estos conocimientos pueden contribuira desarrollar estrategias terapéuticas útiles para prevenir el declinar de la funciónrenal que acontece con el envejecimiento

Frequently underestimated, the deterioration of the renal function characteristicof the aging has very prominent clinical consequences. In the present article someaspects of the cellular and molecular biology of this process are analysed. The criticalrole of the oxidative stress and of TGF �� are underlined. Determinant geneticfactors are also mentioned. Such a knowledge can contribute to develop therapeuticalstrategies to prevent the decline of the renal function that happens withthe aging

Angiotensin II induces a rapid and transient increase of reactive oxygen species.

Vascular smooth muscle cells (VSMC) exhibit a hypertrophic and contractile response after angiotensin II (Ang II) treatment, and the NADH/NADPH oxidase-dependent synthesis of hydrogen peroxide (H(2)O(2)) seems to play a central role in these responses. Present experiments were designed to analyze the mechanisms responsible for the rapid changes induced by Ang II in the intracellular H(2)O(2) concentration in VSMC. Ang II induced a quick and transient increase of dichlorodihydrofluorescein (DCHF) fluorescence in VSMC, an effect that was completely abolished by catalase and by diethyldithiocarbamate, a cell-permeable superoxide dismutase inhibitor. Losartan and pertussis toxin prevented the stimulatory effect of Ang II. Both diphenylene iodonium (NADH/NADPH oxidase blocker) and 3-(4-octadecylbenzoyl)acrylic acid (phospholipase A2 blocker) inhibited the changes in DCHF fluorescence induced by Ang II, in a dose-dependent fashion, and the effects of both inhibitors were additive. These data demonstrate that Ang II induces a very quick and transient increase of H(2)O(2) in VSMC. This effect depends on the receptor type 1, is linked to a G protein, and involves both NADH/NADPH oxidase and phospholipase A2 activation. The mechanism may be related to the previously proposed role of H(2)O(2) in the genesis of the Ang II-induced cell contraction.