Papel del estrés del retículo endoplásmico sobre las alteraciones inducidas por angiotensina II en fibroblastos renales de ratón

Abstract

Angiotensin II (Ang II), the main component of the renin-angiotensin system, plays an essential role in the pathogenesis of renal diseases through the activation of inflammation, fibrosis and oxidative stress. However, the specific mechanisms through Ang II is able to participate in renal damage are not totally established. In recent years, the relevance of the endoplasmic reticulum stress in the inflammatory and profibrotic processes has been proposed. This response is initiated when unfolded proteins are accumulated in the endoplasmic reticulum in response to different stimuli included Ang II. Therefore, the aim of this study was to evaluate the role of endoplasmic reticulum stress in the profibrotic, proinflammatory and prooxidant actions induced by Ang II in murine renal fibroblasts. The data show that Ang II was able to stimulate the protein levels of PDIA6 (Protein disulfide isomerase) and BiP (Binding immunoglobulin protein), two markers of endoplasmic reticulum stress in renal fibroblasts, as well CHOP (C/EBP homologous protein) and ATF6 (Activating transcription factor 6), two pathways involved in this response. In addition, Ang II was able to activate the gene expression of mediators and components of extracellular matrix as well as mediators of inflammatory response and the production of reactive oxygen species. All these responses induced by Ang II were prevented by the presence of the inhibitor of the endoplasmic reticulum stress, the 4- phenylbutyric acid (4-PBA). The results confirmed the capacity of Ang II to activate endoplasmic reticulum stress, to induce oxidative stress and to stimulate fibrosis and inflammation in murine renal fibroblasts. Moreover, 4-PBA is able to prevent the Ang IIinduced alterations in these cells, suggesting that the endoplasmic reticulum stress could mediate the profibrotic, proinflammatory and prooxidant actions of Ang II. Overall, these data highlight the participation of endoplasmic reticulum stress as a possible therapeutic target in renal diseases, specially in which Ang II plays a central role.