Angiotensin III activates nuclear transcription factor-kappaB in cultured mesangial cells mainly via AT(2) receptors: studies with AT(1) receptor-knockout mice.

Nuclear factor-kappaB (NF-kappaB) 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-kappaB in mesangial cells. However, which are the Ang receptor subtypes involved in the NF-kappaB 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 AT(1) and AT(2) receptors. To investigate the receptors involved in the NF-kappaB pathway, two different approaches were used, i.e., pharmacologic studies, using specific AT(1) and AT(2) receptor antagonists and agonists, and studies in AT(1) receptor-knockout mice. In cultured rat mesangial cells, both AT(1) and AT(2) receptor antagonists inhibited AngII-induced NF-kappaB DNA binding activity, whereas NF-kappaB activation elicited by AngIII was mainly blocked by the AT(2) receptor antagonist. Similar results were observed for cytosolic IkappaBalpha degradation. An AT(2) receptor agonist also activated NF-kappaB. In AT(1) receptor-knockout murine mesangial cells, AngIII and AngII increased NF-kappaB activity and degraded cytosolic IkappaBalpha; both processes were blocked by the AT(2) receptor antagonist. These data demonstrate that, in mesangial cells, NF-kappaB activation is mediated by AT(1) and AT(2) receptors, suggesting a novel intracellular signaling mechanism for AT(2) receptors in the kidney. Some differences in Ang peptide receptor-mediated responses were also observed. AngII activates NF-kappaB via AT(1) and AT(2) receptors, whereas AngIII acts mainly via AT(2) receptors. These results suggest the potential involvement of the AngIII/AT(2) receptor/NF-kappaB pathway in pathophysiologic processes in the kidney and provide a better understanding of the renin-angiotensin system.