Reactive oxygen species-mediated signaling pathways in angiotensin II-induced MCP-1 expression of proximal tubular cells.
Angiotensin II (AngII) has pleiotropic effects, the most well known of which is the generation of reactive oxygen species (ROS) and chemokines in inflammatory lesions. Monocyte chemoattractant protein-1 (MCP-1) is considered a major chemokine in the pathogenesis of kidney diseases. We examined signaling pathways of AngII-induced MCP-1 expression and the role of ROS in the murine proximal tubular cells (mProx) using various inhibitors. Furthermore, we compared the signaling pathways between mProx and mesangial cells (MC). AngII-induced MCP-1 protein expression in mProx at 6 h was largely blocked by ROS (N-acetylcysteine; 82 +/- 14%), Ras (N-acetyl-S-trans,trans-farnesyl-L-cysteine; 82 +/- 13%), and nuclear factor-kappaB (NF-kappaB) (parthenolide; 89 +/- 7.9%) inhibitors. Both AT1 receptor (AT1R) (Olmesartan; 41 +/- 12%) and the AT2R (PD123319; 24 +/- 11%) antagonists partially blocked the MCP-1 expression. Furthermore, mitogen-activated protein kinase (MAPK) pathways were also implicated in this protein expression, but it is less dependent on ROS/Ras pathways. In MC, protein kinase (calphostin C; 84 +/- 2.8%) and NF-kappaB (89 +/- 1.4%) inhibitors attenuated acute AngII-induced MCP-1 expression stronger than ROS/Ras inhibitors (1.0 +/- 0.9/29 +/- 9.5%). MAPK pathways, especially p38 MAPK, were involved in MC more than in mProx. AT1R (69 +/- 8.6%) and AT2R (57 +/- 21%) antagonists also were blocked. We suggested that, although NF-kappaB activation has a critical role, signaling pathways are different between mProx and MC. ROS-mediated signaling in mProx may have more contribution to AngII-induced inflammatory responses than to those in MC.
Tanifuji
Chiaki
C
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Suzuki
Yusuke
Y
Geot
Wong Mu
WM
Horikoshi
Satoshi
S
Sugaya
Takeshi
T
Ruiz-Ortega
Marta
M
Egido
Jesus
J
Tomino
Yasuhiko
Y
D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D007684:Kidney Tubules / Q000166:cytology*; D050527:Mesangial Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010084:Oxidation-Reduction; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D018932:Chemokine CCL2; D007093:Imidazoles; D016328:NF-kappa B; D009281:Naphthalenes; D011725:Pyridines; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C437965:olmesartan; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C058819:calphostin C