No abstract

Many experimental data have suggested that the renin-angiotensin system participates in immune and inflammatory responses. Angiotensin II is involved in several steps of the inflammatory process: mononuclear cells respond to angiotensin II stimulation (cell proliferation and chemotaxis); angiotensin II regulates the recruitment of proinflammatory cells into the site of injury (mediated by the expression of vascular permeability factors, adhesion molecules and chemokines by resident cells); inflammatory cells can produce angiotensin II, and might therefore contribute to the perpetuation of tissue damage. In this review, we summarize the proinflammatory properties of angiotensin II, to demonstrate the novel role of this vasoactive peptide as a true cytokine. We will show the information obtained as a result of the pharmacological blockade of the renin angiotensin system, which has demonstrated that this system is involved in immune and inflammatory diseases. In this aspect, we discuss the molecular mechanism of angiotensin II-induced tissue damage, as well as its contribution to the pathogenesis of several diseases, including atherosclerosis, hypertension and renal damage, showing that angiotensin II plays an active role in the inflammatory response of these diseases.

Ang II in vivo increases TNF-alpha production in the kidney. Ang II also up-regulates other proinflammatory mediators, including IL-6, MCP-1 and NF-kappaB, coincidentally associated to the presence of glomerular and interstitial inflammatory cells in the kidney. All these data further strengthen the idea that Ang II plays an active role in the inflammatory response in renal diseases.

Abstract. Inflammatory cell infiltration plays a key role in the onset and progression of renal injury. The NF-B participates in the inflammatory response, regulating many proinflammatory genes. Angiotensin II (Ang II), via AT 1 and AT 2 receptors, activates NF-B. Although the contribution of Ang II to kidney damage progression is already established, the receptor subtype involved in the inflammatory cell recruitment is not clear. For investigating this issue, the unilateral ureteral obstruction (UUO) model was used in mice, blocking Ang II production/ receptors and NF-B pathway. Two days after UUO, obstructed kidneys of wild-type mice presented a marked interstitial inflammatory cell infiltration and increased NF-B activity. Treatment with AT 1 or AT 2 antagonists partially decreased NF-B activation, whereas only the AT 2 blockade diminished monocyte infiltration. Obstructed kidneys of AT 1 -knockout mice showed interstitial monocyte infiltration and NF-B activation; both processes were abolished by an AT 2 antagonist, suggesting AT 2 /NF-B involvement in monocyte recruitment. In wild-type mice, only angiotensin-converting enzyme inhibition or combined therapy with AT 1 plus AT 2 antagonists blocked monocyte infiltration, NF-B activation, and upregulation of NF-B-related proinflammatory genes. Therefore, AT 1 and AT 2 blockade is necessary to arrest completely the inflammatory process. Treatment with two different NF-B inhibitors, pirrolidin-dithiocarbamate and parthenolide, diminished monocyte infiltration and gene overexpression. These data show that Ang II, via AT 1 and AT 2 receptors and NF-B pathway, participates in the regulation of renal monocyte recruitment and may provide a rationale to investigate further the role of AT 2 in human kidney diseases.