TY - JOUR
T1 - Interactions between angiotensin II and NF-κB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy
AU - Lee, Fiona T.H.
AU - Cao, Zemin
AU - Long, David M.
AU - Panagiotopoulos, Sianna
AU - Jerums, George
AU - Cooper, Mark E.
AU - Forbes, Josephine M.
PY - 2004/8/1
Y1 - 2004/8/1
N2 - NF-κB-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-κB is regulated by angiotensin II (AII). However, the role of this pathway in diabetic nephropathy has not been clearly delineated. First, the activation of NF-κB, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-κB, p65, was elevated in the diabetic animals in association with increased MCP-1 gene expression and macrophage infiltration. Second, the effects of treatment for 4 wk with the AII type 1 receptor antagonist valsartan, the AII type 2 receptor antagonist PD123319, or pyrrolidine dithiocarbamate, an inhibitor of NF-κB and on these parameters were assessed. These treatments were associated with a reduction in p65 activation, MCP-1 gene expression, and macrophage infiltration. These findings demonstrate a role for activation of NF-κB, in particular the p65 subunit, in the pathogenesis of early renal macrophage infiltration in experimental diabetes. In the context of the known proinflammatory effects of AII, it is postulated that the renoprotection conferred by angiotensin II receptor antagonism is at least partly related to the inhibition of NF-κB-dependent pathways.
AB - NF-κB-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-κB is regulated by angiotensin II (AII). However, the role of this pathway in diabetic nephropathy has not been clearly delineated. First, the activation of NF-κB, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-κB, p65, was elevated in the diabetic animals in association with increased MCP-1 gene expression and macrophage infiltration. Second, the effects of treatment for 4 wk with the AII type 1 receptor antagonist valsartan, the AII type 2 receptor antagonist PD123319, or pyrrolidine dithiocarbamate, an inhibitor of NF-κB and on these parameters were assessed. These treatments were associated with a reduction in p65 activation, MCP-1 gene expression, and macrophage infiltration. These findings demonstrate a role for activation of NF-κB, in particular the p65 subunit, in the pathogenesis of early renal macrophage infiltration in experimental diabetes. In the context of the known proinflammatory effects of AII, it is postulated that the renoprotection conferred by angiotensin II receptor antagonism is at least partly related to the inhibition of NF-κB-dependent pathways.
UR - http://www.scopus.com/inward/record.url?scp=3543069402&partnerID=8YFLogxK
U2 - 10.1097/01.ASN.0000135055.61833.A8
DO - 10.1097/01.ASN.0000135055.61833.A8
M3 - Article
C2 - 15284299
AN - SCOPUS:3543069402
VL - 15
SP - 2139
EP - 2151
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 8
ER -