Effect of simultaneous blockade of AT1 and AT2 receptors on the NFkappaB 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 (AT1) and type 2 (AT2) receptors are involved in the NFkappaB pathway; however, some aspects remain mysterious. AT1 antagonists increased plasma Ang II levels that could bind to AT2, so understanding the clinical importance of AT2 stimulation or inhibition is an interesting unresolved point. METHODS: Experiments were done in wild-type (WT) and AT1a receptor knockout mice that received subcutaneous Ang II infusions (1000 ng/kg/min) for 3 days. Specific blockers of AT1 (losartan 10 mg/kg/day) and AT2 (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 AT1 or AT2 antagonists. In AT1 knockout mice, Ang II also activated renal NFkappaB, which was only blocked by the AT2 antagonist. Both Ang II-infused WT and AT1 knockout mice showed inflammatory infiltration in tubulointerstitial areas that were suppressed by the AT2, but not AT1, antagonist. Combined therapy of both AT1 and AT2 antagonists blocked renal NFkappaB activation and inflammatory cell infiltration, both in WT and in AT1 knockout mice. CONCLUSION: Ang II, via AT1 and AT2 stimulation, leads to NFkappaB activation that was only blocked by combined therapy with both antagonists. The participation of AT2 receptors in the recruitment of inflammatory cells underscores the need of future studies that evaluate the clinical usefulness of this strategy.