Effect of simultaneous blockade of AT1 and AT2 receptors on the NFκB pathway and renal inflammatory response

Background. Angiotensin II (Ang II) is a cytokine that participates in the inflammatory response. The nuclear factor kappa B (NFkappaB) is involved in the regulation of many immune and inflammatory factors. Different works have shown that both angiotensin II receptor type 1 (AT(1)) and type 2 (AT(2)) receptors are involved in the NFkappaB pathway; however, some aspects remain mysterious. AT(1) antagonists increased plasma Ang II levels that could bind to AT(2), so understanding the clinical importance of AT(2) stimulation or inhibition is an interesting unresolved point. Methods. Experiments were done in wild-type (WT) and AT(1a) receptor knockout mice that received subcutaneous Ang II infusions (1000 ng/kg/min) for 3 days. Specific blockers of AT(1) (losartan 10 mg/kg/day) and AT(2) (PD123319 30 mg/kg/day) receptors were administered 1 day before and during Ang II infusion. NFkappaB activity was examined by electrophoretic mobility assay and inflammatory (monocyte/macrophage) cell infiltration by immunohistochemistry. Results. In WT mice, Ang II infusion caused renal NFkappaB activation that was partially diminished by either AT(1) or AT(2) antagonists. In AT(1) knockout mice, Ang II also activated renal NFkappaB, which was only blocked by the AT(2) antagonist. Both Ang II-infused WT and AT(1) knockout mice showed inflammatory infiltration in tubulointerstitial areas that were suppressed by the AT(2), but not AT(1), antagonist. Combined therapy of both AT(1) and AT(2) antagonists blocked renal NFkappaB activation and inflammatory cell infiltration, both in WT and in AT(1) knockout mice. Conclusion. Ang II, via AT(1) and AT(2) stimulation, leads to NFkappaB activation that was only blocked by combined therapy with both antagonists. The participation of AT(2) receptors in the recruitment of inflammatory cells underscores the need of future studies that evaluate the clinical usefulness of this strategy.