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Angiotensin III Activates Nuclear Transcription Factor-B in Cultured Mesangial Cells Mainly via AT₂ Receptors: Studies with AT₁ Receptor-Knockout Mice

Óscar Lorenzo^*, Marta Ruiz-Ortega^*, Yusuke Suzuki^*, Mónica Rupérez^*, Vanesa Esteban^*, Takeshi Sugaya and Jesús Egido^*

*Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain; Discovery Research Laboratory, Tanabe Seiyaku Corp. Ltd., Osaka, Japan.

Correspondence to Dr. Marta Ruiz-Ortega, Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain. Phone: 34-91-550-48-00; Fax: 34-91-549-47-64; E-mail: mruizo{at}fjd.es

ABSTRACT. Nuclear factor-B (NF-B) regulates many genes involved in renal pathophysiologic processes. It was previously demonstrated that angiotensin II (AngII) and its amino-terminal degradation product AngIII activate NF-B in mesangial cells. However, which are the Ang receptor subtypes involved in the NF-B pathway and whether these Ang peptides act through the same or different receptors in mesangial cells have not been evaluated. Under the culture conditions used, quiescent rat mesangial cells expressed both AT₁ and AT₂ receptors. To investigate the receptors involved in the NF-B pathway, two different approaches were used, i.e., pharmacologic studies, using specific AT₁ and AT₂ receptor antagonists and agonists, and studies in AT₁ receptor-knockout mice. In cultured rat mesangial cells, both AT₁ and AT₂ receptor antagonists inhibited AngII-induced NF-B DNA binding activity, whereas NF-B activation elicited by AngIII was mainly blocked by the AT₂ receptor antagonist. Similar results were observed for cytosolic IB degradation. An AT₂ receptor agonist also activated NF-B. In AT₁ receptor-knockout murine mesangial cells, AngIII and AngII increased NF-B activity and degraded cytosolic IB; both processes were blocked by the AT₂ receptor antagonist. These data demonstrate that, in mesangial cells, NF-B activation is mediated by AT₁ and AT₂ receptors, suggesting a novel intracellular signaling mechanism for AT₂ receptors in the kidney. Some differences in Ang peptide receptor-mediated responses were also observed. AngII activates NF-B via AT₁ and AT₂ receptors, whereas AngIII acts mainly via AT₂ receptors. These results suggest the potential involvement of the AngIII/AT₂ receptor/NF-B pathway in pathophysiologic processes in the kidney and provide a better understanding of the renin-angiotensin system.

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