Monocyte chemoattractant protein (MCP)-1 is closely related to the pathogenesis of the progression of various chronic renal diseases, including IgA nephropathy (IgAN), through its chemoattractant effect on macrophages. However, the correlation of MCP-1 gene polymorphism with the long-term prognosis of Japanese patients with IgAN has not been clearly determined yet.
We investigated 277 Japanese patients diagnosed with IgAN based on renal biopsy to clarify the association between the progression of IgAN and MCP-1 gene polymorphism at position A-2518G, which regulates the transcription of the MCP-1 gene.
The incidence of endstage renal disease was significantly higher in patients with the AA genotype (47.1%) compared to those with the AG (24.1%) or GG (27.4%) genotype (P = 0.024). Moreover, Kaplan-Meier analysis revealed that the AA genotype significantly facilitated the progression of renal disease (log rank; P = 0.0029), and Cox proportional hazards regression model analysis showed that the AA genotype represented a 2.058-fold risk for the progression of renal disease (P = 0.026) compared to the AG/GG genotype. However, when the patients were treated with angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, or corticosteroid, homozygosity for the -2518A allele was not associated with a higher rate of incidence of endstage renal disease. Serum MCP-1 levels were higher although not significantly so, in the patients with IgAN possessing the AA genotype.
The AA genotype at MCP-1 -2518 was an independent risk factor for the progression of renal disease in Japanese patients with IgAN, and was closely associated with renal survival.
Holdsworth, SR, Neale, TJ, Wilson, CB 1981Abrogation of macrophage-dependent injury in experimental glomerulonephritis in the rabbit. Use of an antimacrophage serumJ Clin Invest6868698PubMedCrossRefGoogle Scholar
Tesch, GH, Schwarting, A, Kinoshita, K, Lan, HY, Rollins, BJ, Kelley, VR 1999Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritisJ Clin Invest1037380PubMedCrossRefGoogle Scholar
Baggiolini, M, Dewald, B, Moser, B 1994Interleukin-8 and related chemotactic cytokines – CXC and CC chemokinesAdv Immunol5597179PubMedCrossRefGoogle Scholar
Viedt, C, Orth, SR 2002Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does it more than simply attract monocytes?Nephrol Dial Transplant1720437PubMedCrossRefGoogle Scholar
Segerer, S, Nelson, PJ, Schlöndorff, D 2000Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studiesJ Am Soc Nephrol1115276PubMedGoogle Scholar
Viedt, C, Dechend, R, Fei, J, Hänsch, GM, Kreuzer, J, Orth, SR 2002MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-κB and activating protein-1J Am Soc Nephrol13153447CrossRefPubMedGoogle Scholar
Viedt, C, Vogel, J, Athanasiou, T, Shen, W, Orth, SR, Kübler, W, et al. 2002Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle cells by differential activation of nuclear factor-κB and activator protein-1Arterioscler Thromb Vasc Biol2291420PubMedCrossRefGoogle Scholar
Ueda, A, Okuda, K, Ohno, S, Shirai, A, Igarashi, T, Matsunaga, K, et al. 1994NF-κB and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 geneJ Immunol153205263PubMedGoogle Scholar
Rovin, BH, Lu, L, Saxena, R 1999A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expressionBiochem Biophys Res Commun2593448CrossRefPubMedGoogle Scholar
Steinmetz, OM, Panzer, U, Harendza, S, Mertens, PR, Ostendorf, T, Floege, J, et al. 2004No association of the −2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathyNephrol Dial Transplant19596601PubMedCrossRefGoogle Scholar
Krüger, B, Schröppel, B, Ashkan, R, Marder, B, Zülke, C, Murphy, B, et al. 2002A monocyte chemoattractant protein-1 (MCP-1) polymorphism and outcome after renal transplantationJ Am Soc Nephrol1325859PubMedCrossRefGoogle Scholar
Kim, HL, Lee, DS, Yang, SH, Lim, CS, Chung, JH, Kim, S, et al. 2002The polymorphism of monocyte chemoattractant protein-1 is associated with the renal disease of SLEAm J Kidney Dis40114652PubMedCrossRefGoogle Scholar
Omori, K, Kazama, JJ, Song, J, Goto, S, Takada, T, Saito, N, et al. 2002Association of the MCP-1 gene polymorphism A-2518G with carpal-tunnel syndrome in hemodialysis patientsAmyloid917582PubMedGoogle Scholar
Narita, I, Goto, S, Saito, N, Song, J, Kondo, D, Omori, K, et al. 2003Genetic polymorphism of NPHS1 modifies the clinical manifestations of Ig A nephropathyLab Invest831193200CrossRefPubMedGoogle Scholar
Prodjosudjadi, W, Gerritsma, JSJ, van Es, LA, Daha, MR, Bruijn, JA 1995Monocyte chemoattractant protein-1 in normal and diseased human kidneys: an immunohistochemical analysisClin Nephrol4414855PubMedGoogle Scholar
Prodjosudjadi, W, Gerritsma, JSJ, Klar-Mohamad, N, Gerritsen, AF, Bruijn, JA, Daha, MR, et al. 1995Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cellsKidney Int48147786PubMedCrossRefGoogle Scholar
Mezzano, SA, Barria, M, Droguett, MA, Burgos, ME, Ardiles, LG, Flores, C, et al. 2001Tubular NF-κB and AP-1 activation in human proteinuric renal diseaseKidney Int60136677PubMedCrossRefGoogle Scholar
Wada, T, Yokoyama, H, Su, SB, Mukaida, N, Iwano, M, Dohi, K, et al. 1996Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritisKidney Int497617PubMedCrossRefGoogle Scholar
Wada, T, Furuichi, K, Sakai, N, Iwata, Y, Yoshimoto, K, Shimizu, M, et al. 2000Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathyKidney Int5814929CrossRefPubMedGoogle Scholar
Grandaliano, G, Gesualdo, L, Ranieri, E, Monno, R, Montinaro, V, Marra, F, et al. 1996Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitmentJ Am Soc Nephrol790613PubMedGoogle Scholar
Levy, M, Berger, J 1988Worldwide perspective of IgA nephropathyAm J Kidney Dis123407PubMedGoogle Scholar
Narita, I, Goto, S, Saito, N, Song, J, Omori, K, Kondo, D, et al. 2003Angiotensinogen gene variation and renoprotective efficacy of renin-angiotensin system blockade in IgA nephropathyKidney Int6410508CrossRefPubMedGoogle Scholar
Ruiz-Ortega, M, Bustos, C, Hernández-Presa, MA, Lorenzo, O, Plaza, JJ, Egido, J 1998Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-κB activation and monocyte chemoattractant protein-1 synthesisJ Immunol1614309PubMedGoogle Scholar
Tang, WW, Yin, S, Wittwer, AJ, Qi, M 1995Chemokine gene expression in anti-glomerular basement membrane antibody glomerulonephritisAm J Physiol269F32330PubMedGoogle Scholar