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

Vanesa Esteban^*, Oscar Lorenzo^*, Mónica Rupérez^*, Yusuke Suzuki, Sergio Mezzano, Julia Blanco, Mathias Kretzler^||, Takeshi Sugaya, Jesús Egido^* and Marta Ruiz-Ortega^*

*Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Division of Nephrology, Juntendo University, Japan; Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile; Hospital Clínico de San Carlos, Madrid, Spain; and ^||Nephrology Center, University of Munich, Munich, Germany

Correspondence to Dr. Marta Ruiz-Ortega, Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid, Spain. Phone: 34-91-550-48-00, ext 3168; Fax: 34-91-5442636; E-mail: mruizo{at}fjd.es

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 AT₁ and AT₂ 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 AT₁ or AT₂ antagonists partially decreased NF-B activation, whereas only the AT₂ blockade diminished monocyte infiltration. Obstructed kidneys of AT₁-knockout mice showed interstitial monocyte infiltration and NF-B activation; both processes were abolished by an AT₂ antagonist, suggesting AT₂/NF-B involvement in monocyte recruitment. In wild-type mice, only angiotensin-converting enzyme inhibition or combined therapy with AT₁ plus AT₂ antagonists blocked monocyte infiltration, NF-B activation, and upregulation of NF-B–related proinflammatory genes. Therefore, AT₁ and AT₂ 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 AT₁ and AT₂ receptors and NF-B pathway, participates in the regulation of renal monocyte recruitment and may provide a rationale to investigate further the role of AT₂ in human kidney diseases.

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