Monocyte chemoattractant protein-1 (MCP-1) plays an important role in glomerulonephritis and nitric oxide (NO) exerts a variety of renal pathophysiological effects. We investigated the effect of exogenous NO on pro-inflammatory cytokine-induced MCP-1 expression in human mesangial cells and its signal transduction pathway. Cells were pretreated with NO donors such as 3-morpholino-sydnonimine (SIN-1) or nitroprusside, and then stimulated with tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). MCP-1 expression of mRNA and protein were measured by Northern blot analysis and ELISA. NF-ĸB binding activity was determined by electrophoretic mobility shift assay. Degradation of IĸB-α protein was assessed by Western blot analysis. SIN-1 inhibited TNF-α- or IL-1β-induced MCP-1 mRNA expression in a dose-dependent manner and also suppressed the MCP-1 protein expression. Nitroprusside inhibited the MCP-1 mRNA expression as well. SIN-1 dose dependently inhibited the TNF-α- or IL-1β-induced NF-ĸB binding activity and suppressed the TNF-α-induced degradation of IĸB-α. Analogue of cGMP (8-bromo-cGMP) had no significant effect on TNF-α-induced MCP-1 mRNA expression and guanylate cyclase inhibitor (ODQ) also had no significant influence on the inhibitory effect of SIN-1. These results suggest that exogenous NO inhibits MCP-1 expression via suppression of NF-ĸB by reducing the degradation of IĸB-α and through a cGMP-independent pathway.

Keywords:
IĸB-alpha, Mesangial cells, Monocytechemoattractant protein-1, Nuclear factor-ĸB, 3-Morpholino-sydnonimine
1.
Atkins RC: Macrophages in renal injury. Am J Kidney Dis 1998;31:45–47.
2.
Leonard EJ, Yoshimura T: Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 1990;11:97–101.
3.
Rollins BJ, Walz A, Baggiolini M: Recombinant human MCP-1/JE induces chemotaxis, calcium flux and the respiratory burst in human monocytes. Blood 1991;78:1112–1116.
4.
Jiang Y, Beller DI, Frendl G, Graves DT: Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 1992;148:2423–2428.
5.
Gharaee-Kermani M, Denholm EM, Phan SH: Costimulation of fibroblast collagen and transforming growth factor beta 1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996;271:17779–17784.
6.
Rovin BH, Rumancik M, Tan L, Dickerson J: Glomerular expression of monocyte chemoattractant protein-1 in experimental and human glomerulonephritis. Lab Invest 1994;71:536–542.
7.
Stahl RAK: Chemoattractive (chemokine) and immune renal injury. Nephrol Dial Transplant 1995;10:307–319.
8.
Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Eng J Med 1993;329:2002–2012.
9.
Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA: Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci USA 1994;91:2046–2050.
10.
Ashab I, Peer G, Blum M, Wollman Y, Chernihovsky T, Hassner A, Schwartz D, Cabili S, Silverberg D, Iaina A: Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int 1995;47:1515–1521.
11.
Maree A, Peer G, Iaina A, Blum M, Wollman Y, Chernihovsky T, Silverberg DS, Cabili S: Nitric oxide in streptozotocin-induced diabetes melitus in rats. Clin Sci 1996;90:379–384.
12.
Reyes AA, Purkerson ML, Karl I, Klahs S: Dietary supplementation with L-arginine ameliorates the progression of renal disease in rats with subtotal nephrectomy. Am J Kidney Dis 1992;20:168–176.
13.
Hertzan-Levy S, Fish R, Skutelsky E, Wollman Y, Chernihovsky T, Polak-Charcon S, Schwartz D, Blum M, Cabili S, Iaina A: Glomerular basement membrane anion sites in adriamycin nephropathy: Effect of saline loading and nitric oxide modulation. Nephron 2000;84:354–361.
14.
Shyy YJ, Li YS, Kolattukudy PE: Activation of MCP-1 gene expression is mediated through multiple signaling pathways. Biochem Biophys Res Comm 1993;192:693–699.
15.
Wardle EN: Nuclear factor κB for the nephrologist. Nephrol Dial Transplant 2001;16:1764–1768.
16.
Ikeda M, Ikeda U, Takahashi M, Shimada K, Minota S, Kano S: Nitric oxide inhibits intracellular adhesion molecule-1 expression in rat mesangial cells. J Am Soc Nephrol 1996;7:2213–2218.
17.
De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK: Nitric oxide decreases cytokine-induced endothelial activation: Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60–68.
18.
Peng HB, Libby P, Liao JK: Induction and stabilization of IκB-α by nitric oxide mediates inhibition of NF-κB. J Biol Chem 1995;270:14214–14219.
19.
Lee SK, Kim BS, Yang WS, Kim SB, Park SK, Park JS: High glucose induces MCP-1 expression partly via tyrosine kinase-AP-1 pathway in peritoneal mesothelial cells. Kidney Int 2001;60:55–64.
20.
Nelken NA, Coughlin SR, Gordon D, Wilcox JN: Monocyte chemoattractant protein-1 in human atheromatous plaque. J Clin Invest 1991;88:1121–1127.
21.
Graves DT, Barnhill R, Galanopoulos T, Antoniades HN: Expression of monocyte chemotactic protein-1 (MCP-1) in human melanoma in vivo. Am J Pathol 1992;140:9–14.
22.
Cattel V: Nitrix oxide and glomerulonephritis. Semin Nephrol 1999;19:277–287.
23.
Ketteler M, Distler A: The role of nitric oxide in experimental glomerulonephritis. Kidney Blood Press Res 1996;19:177–181.
24.
Garcia-Criado FJ, Eleno N, Santos-Benito F, Valduniciel JJ, Reverte M, Lozano-Sanchez FS, Ludena MD, Gomez-Alonso, Lopez-Novoa JM: Protective effect of exogenous nitric oxide on the renal function and inflammatory response in a model of ischemia-reperfusion. Transplantation 1998;66:982–990
25.
Westberg G, Schulz PJ, Raij L: Exogenous nitric oxide prevents endotoxin-induced glomerular thrombosis in rats. Kidney Int 1994;46:711–716.
26.
Otsuka Y, Harasawa S, Sugiura H, Koike M, Akimoto H, Ishii T, Abeta H, Okabe T, Kushiro T, Kanmatsuse K: The effect of exogenous nitric oxide on endothelial dysfunction in two-kidney, one-clip renovascular hypertensive rats. Jpn J Nephrol 2000;42:619–624.
27.
Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R: Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 1995:76:980–986.
28.
Tsao PS, Wang BY, Buitrago R, Shyy JYJ, Cooke JP: Nitric oxide regulates monocyte chemotactic protein-1. Circulation 1997;96:934–940.
29.
Yao J, Schoecklmann HO, Prols F, Gauer S, Sterzel RB: Exogenous nitric oxide inhibits mesangial cell adhesion to extracellular matrix components. Kidney Int 1998;53:598–608.
30.
Craven PA, Studer RK, Felder J, Phillips S, Derubertis FR: Nitric oxide inhibition of transforming growth factor-β and collagen synthesis in mesangial cells. Diabetes 1997;46:671–681.
31.
Diaz-Cazorla, Perez-Sala, Lamas S: Dual effect of nitric oxide donors on cyclooxgenase-2 expression in human mesangial cells. J Am Soc Nephrol 1999;10:943–952.
32.
Mitsutomi N, Akashi C, Odagiri J, Matsumura Y: Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. Eur J Pharmacol 1999;364:65–73.
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2002
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