The renin angiotensin system RAS is a
The renin-angiotensin system (RAS) is a hormonal system which plays a role in the regulation of blood pressure and body fluid resveratrol . The main bioactive peptide of RAS is angiotensin II (Ang II) whose biological functions are interposed through angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). The AT2R has been proposed to counteract the AT1R mediated function . It has been reported that RAS plays a potential role in regulating the differentiation of stem cells. The RAS has been reported to be expressed in many organs. Additionally, it has been hypothesized that the local RAS exerts paracrine/autocrine functions on MSCs, directing them to differentiate into specialized cells; such as cardiomyocytes, smooth muscle cells, and adipocytes; during tissue repair and regeneration , , . Previous studies reported that AT1R and AT2R have opposing effects on the differentiation of MSCs. The activation of AT1R was reported to inhibit the differentiation of MSCs into cardiomyocytes, whereas AT2R activation induced the cardiomyocyte formation . On the other hand, AT1R activation induced the differentiation of MSCs into adipocytes, while the activation of AT2R inhibited adipocyte generation . It is unclear why the activation of AT1R or AT2R induces the differentiation of MSCs into specific cell type rather than another, this is presumably due to the specificity of particular cell types or other unstudied factors .
Materials and methods
Discussion To our knowledge, the current study is the first to investigate the role of local RAS in the differentiation of BM-derived MSCs into IPCs, aiming to provide information which may contribute to promoting the IPCs production from MSCs. The role of local RAS in cell development presents great potential in the field of stem cell and regenerative medicine. One of the promising therapeutic strategies to mitigate pathophysiological conditions of DM is the blockade of RAS , , . The present study confirmed previous findings that rat BM-derived MSCs contain local RAS , . We also studied the change in expression of different components of RAS during the differentiation of MSCs into IPCs. Expression of angiotensinogen, ACE, and renin mRNA was up-regulated during the differentiation of MSCs into IPCs. This explains our finding that Ang II production is increased during the differentiation of MSCs into IPCs. Our observations also revealed that expression of AT1R mRNA in differentiated MSCs was undetectable while expression of AT2R mRNA in differentiated MSCs has been increased. Our data would hypothesize that local RAS regulates the differentiation of MSCs into IPCs mainly through AT2R activation. Moreover, our data revealed that during the differentiation process, PDX-1 and MafA expression and insulin level have been increased in MSCs treated with AT1R blocker indicating that the MSCs have been differentiated into IPCs, while in MSCs treated with AT2R blocker alone or treated with both blockers, these parameters have not been changed indicating that the MSCs have been not differentiated into IPCs. These findings strengthen our previous hypothesis that the role of local RAS in the differentiation of MSCs into IPCs is mainly through AT2R activation. Our results are in accordance with the results of a recent study which investigated the RAS during the development of mouse pancreas and reported that the antagonism of pancreatic AT2R down-regulated the expression of insulin mRNA after seven days of culture, and lead to decreasing the differentiation of pancreatic progenitor cells into β-cell lineage. Furthermore, RAS components, in particular, AT2R, are present in the developing pancreas, and there is an increase in the expression of AT2R in the developing pancreas, indicating a master role of AT2R within the β-cell lineage and thus its contribution to regulating the development of pancreas .