Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis

被引:45
作者
Budisavljevic, MN
Hodge, L
Barber, K
Fulmer, JR
Durazo-Arvizu, RA
Self, SE
Kuhlmann, M
Raymond, JR
Greene, EL
机构
[1] Med Univ S Carolina, Div Nephrol, Charleston, SC 29425 USA
[2] Med Univ S Carolina, Dept Biometry, Charleston, SC 29425 USA
[3] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA
[4] Ralph H Johnson Vet Affairs Med Ctr, Med Serv, Charleston, SC 29425 USA
[5] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29425 USA
[6] Univ Saarlandes Kliniken, Dept Internal Med, D-66421 Homburg, Germany
[7] Mayo Clin & Mayo Fdn, Dept Med, Div Nephrol, Rochester, MN 55905 USA
关键词
alpha-lipoic acid; anti-Thy; 1; nephritis; extracellular signal-regulated kinase; alpha-smooth muscle actin; transforming growth factor-beta(1);
D O I
10.1152/ajprenal.00397.2002
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Reactive oxygen species (ROS) are increasingly believed to be important intracellular signaling molecules in mitogenic pathways involved in the pathogenesis of glomerulonephritis (GN). We explored the effects of the antioxidants alpha-lipoic acid and N-acetyl-L-cysteine on ERK activation in cultured mesangial cells and the role of ERK activation in the severity of glomerular injury in a rat model of anti-Thy 1 GN. In cultured mesangial cells, growth factors stimulated ERK phosphorylation by 150 - 450%. Antioxidants reduced this increase by 50 - 60%. Induction of anti-Thy 1 nephritis in rats led to a 210% increase in glomerular ERK phosphorylation. This increase in phosphorylated ERK was reduced by 50% in animals treated with alpha-lipoic acid. Treatment with alpha-lipoic acid resulted in significant improvement of glomerular injury. Cellular proliferation was reduced by 100%, and the number of proliferating cell nuclear antigen-positive cells was reduced by 64%. The increased expression of glomerular transforming growth factor-beta(1) protein and mRNA in rats with anti-Thy 1 nephritis was significantly attenuated and mesangial cell transformation into myofibroblasts was completely prevented by treatment with alpha-lipoic acid. The effects of alpha-lipoic acid were at least partially due to inhibition of oxidative stress. In rats with anti-Thy 1 nephritis, ROS production was increased 400 - 500%, and this increase was inhibited by 55% by treatment with alpha-lipoic acid. We suggest that ROS may mediate glomerular injury by inducing ERK phosphorylation. alpha-Lipoic acid should be considered a potential therapeutic agent in certain types of human GN.
引用
收藏
页码:F1138 / F1148
页数:11
相关论文
共 40 条
  • [1] ENHANCED EXPRESSION OF MUSCLE-SPECIFIC ACTIN IN GLOMERULONEPHRITIS
    ALPERS, CE
    HUDKINS, KL
    GOWN, AM
    JOHNSON, RJ
    [J]. KIDNEY INTERNATIONAL, 1992, 41 (05) : 1134 - 1142
  • [2] The pharmacology of the antioxidant lipoic acid
    Biewenga, GP
    Haenen, GRMM
    Bast, A
    [J]. GENERAL PHARMACOLOGY, 1997, 29 (03): : 315 - 331
  • [3] In vivo identification of the mitogen-activated protein kinase cascade as a central pathogenic pathway in experimental mesangioproliferative glomerulonephritis
    Bokemeyer, D
    Panek, D
    Kramer, HJ
    Lindemann, M
    Kitahara, M
    Boor, P
    Kerjaschki, D
    Trzaskos, JM
    Floege, J
    Ostendorf, T
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2002, 13 (06): : 1473 - 1480
  • [4] Bokemeyer D, 2000, J AM SOC NEPHROL, V11, P232, DOI 10.1681/ASN.V112232
  • [5] Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats
    Bokemeyer, D
    Guglielmi, KE
    McGinty, A
    Sorokin, A
    Lianos, EA
    Dunn, MJ
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (03) : 582 - 588
  • [6] Multiple intracellular MAP kinase signaling cascades
    Bokemeyer, D
    Sorokin, A
    Dunn, MJ
    [J]. KIDNEY INTERNATIONAL, 1996, 49 (05) : 1187 - 1198
  • [7] MECHANISMS OF PROGRESSIVE RENAL DISEASE IN GLOMERULONEPHRITIS
    COUSER, WG
    JOHNSON, RJ
    [J]. AMERICAN JOURNAL OF KIDNEY DISEASES, 1994, 23 (02) : 193 - 198
  • [8] ACTIVATION OF MAP KINASE KINASE IS NECESSARY AND SUFFICIENT FOR PC12 DIFFERENTIATION AND FOR TRANSFORMATION OF NIH 3T3 CELLS
    COWLEY, S
    PATERSON, H
    KEMP, P
    MARSHALL, CJ
    [J]. CELL, 1994, 77 (06) : 841 - 852
  • [9] Glomerular oxidative and antioxidative systems in experimental mesangioproliferative glomerulonephritis
    Gaertner, SA
    Janssen, U
    Ostendorf, T
    Koch, KM
    Floege, J
    Gwinner, W
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2002, 13 (12): : 2930 - 2937
  • [10] Organization and regulation of mitogen-activated protein kinase signaling pathways
    Garrington, TP
    Johnson, GL
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1999, 11 (02) : 211 - 218