Systemic infusion of angiotensin II into normal rats activates nuclear factor-kappaB and AP-1 in the kidney: role of AT(1) and AT(2) receptors.
Recent studies have pointed out the implication of angiotensin II (Ang II) in various pathological settings. However, the molecular mechanisms and the AngII receptor (AT) subtypes involved are not fully identified. We investigated whether AngII elicited the in vivo activation of nuclear transcription factors that play important roles in the pathogenesis of renal and vascular injury. Systemic infusion of Ang II into normal rats increased renal nuclear factor (NF)-kappaB and AP-1 binding activity that was associated with inflammatory cell infiltration and tubular damage. Interestingly, infiltrating cells presented activated NF-kappaB complexes, suggesting the involvement of AngII in inflammatory cell activation. When rats were treated with AT(1) or AT(2) receptor antagonists different responses were observed. The AT(1) antagonist diminished NF-kappaB activity in glomerular and tubular cells and abolished AP-1 in renal cells, improved tubular damage and normalized the arterial blood pressure. The AT(2) antagonist diminished mononuclear cell infiltration and NF-kappaB activity in glomerular and inflammatory cells, without any effect on AP-1 and blood pressure. These data suggest that AT(1) mainly mediates tubular injury via AP-1/NF-kappaB, whereas AT(2) receptor participates in the inflammatory cell infiltration in the kidney by NF-kappaB. Our results provide novel information on AngII receptor signaling and support the recent view of Ang II as a proinflammatory modulator.
Ruiz-Ortega
M
M
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain. mruizo@fjd.es
Lorenzo
O
O
Rupérez
M
M
Blanco
J
J
Egido
J
J
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007260:Infusion Pumps; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D018808:Transcription Factor AP-1; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan