Angiotensin II, the immune system and renal diseases: another road for RAS?

Recent findings from large clinical trials and experimental studies have emphasized the importance of inhibiting the renin–angiotensin system (RAS) in a wide variety of diseases. They have demonstrated that the benefits of RAS blockade may be due to the inhibition of pressor and non-pressor actions of RAS. Since elevated tissue levels of RAS components have been demonstrated in many diseases, the potential contribution of local RAS to the progression of immune and non-immune conditions has been considered in recent years. Novel components of RAS, such as a renin receptor [1] and an angiotensinconverting enzyme (ACE) 2 molecule [2], have been described in several organs, further indicating that resident and infiltrating cells possess the enzymatic machinery to perform the complete conversion to active angiotensin II (Ang II). Therefore, RAS effects may be partly dependent on the compartment in which Ang II, its major effector peptide, is generated. There is at present a considerable amount of data indicating pleiotropic effects of Ang II [3]. One of the well-described Ang II actions is as a growth factor that regulates cell growth and fibrosis [4]. Special attention has been paid to transforming growth factorin Ang II-mediated fibrosis and hypertrophy [4]. This aspect affords an additional therapeutic rationale to the RAS blockade in progressive renal diseases independently of the aetiology. However, increasing evidence indicates that RAS may participate not only in the progression, but also in the induction of several diseases [5]. This idea is partly based on the Ang II-related leukocyte extravasation, which is divided into two steps: (i) margination through rolling and adhesion and (ii) migration toward chemotactic stimuli. Clinical and experimental studies have demonstrated that Ang II is involved in the regulation of adhesion molecule expression in many diseases [5]. In addition, Ang II enhances chemokine and chemokine receptor expression in various tissues and cell types [5], suggesting a role of RAS in leukocyte infiltration. Moreover, immunocompetent cells, including T lymphocytes, macrophages and dendritic cells, are equipped with components of the RAS and can participate in the production of Ang II [5–7]. These findings lead to the notion that RAS may influence the prognosis of many renal diseases in association with immune system activation.