title: Reactive oxygen species-mediated signaling pathways in angiotensin II-induced MCP-1 expression of proximal tubular cells.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanifuji
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Wong Mu
authors.initials: WM
authors.lastname: Geot
authors.forename: Satoshi
authors.initials: S
authors.lastname: Horikoshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: 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
chemical_list: 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