Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy.
NF-kappaB-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-kappaB 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-kappaB, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-kappaB, 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-kappaB 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-kappaB, 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-kappaB-dependent pathways.
Danielle Alberti Memorial Centre for Diabetic Complications, Vascular Division, Baker Medical Research Institute, Melbourne 8008, Australia.
Fiona T H
FT
Lee
Zemin
Z
Cao
David M
DM
Long
Sianna
S
Panagiotopoulos
George
G
Jerums
Mark E
ME
Cooper
Josephine M
JM
Forbes
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers; D018932:Chemokine CCL2 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000975:Antioxidants; D015415:Biomarkers; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606206:Nfkbia protein, rat; D011759:Pyrrolidines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid