Angiotensin II, via AT1 and AT2 Receptors and NF-κB Pathway, Regulates the Inflammatory Response in Unilateral Ureteral Obstruction

Abstract

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.

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TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function

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A Sphingosine Kinase-1 Inhibitor, SKI-II, Induces Growth Inhibition and Apoptosis in Human Gastric Cancer Cells

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