Angiotensin III Activates Nuclear Transcription Factor-κB in Cultured Mesangial Cells Mainly via AT2Receptors: Studies with AT1Receptor-Knockout Mice

ABSTRACT. Nuclear factor-κB (NF-κB) 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-κB in mesangial cells. However, which are the Ang receptor subtypes involved in the NF-κB 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 AT1and AT2receptors. To investigate the receptors involved in the NF-κB pathway, two different approaches were used,i.e., pharmacologic studies, using specific AT1and AT2receptor antagonists and agonists, and studies in AT1receptor-knockout mice. In cultured rat mesangial cells, both AT1and AT2receptor antagonists inhibited AngII-induced NF-κB DNA binding activity, whereas NF-κB activation elicited by AngIII was mainly blocked by the AT2receptor antagonist. Similar results were observed for cytosolic IκBα degradation. An AT2receptor agonist also activated NF-κB. In AT1receptor-knockout murine mesangial cells, AngIII and AngII increased NF-κB activity and degraded cytosolic IκBα; both processes were blocked by the AT2receptor antagonist. These data demonstrate that, in mesangial cells, NF-κB activation is mediated by AT1and AT2receptors, suggesting a novel intracellular signaling mechanism for AT2receptors in the kidney. Some differences in Ang peptide receptor-mediated responses were also observed. AngII activates NF-κB via AT1and AT2receptors, whereas AngIII acts mainly via AT2receptors. These results suggest the potential involvement of the AngIII/AT2receptor/NF-κB pathway in pathophysiologic processes in the kidney and provide a better understanding of the renin-angiotensin system.