Cytokine-induced expression of tPA is differentially modulated by NO and ROS in rat mesangial cells

被引:30
作者
Eberhardt, W [1 ]
Beck, KF [1 ]
Pfeilschifter, J [1 ]
机构
[1] Klinikum Johann Wolfgang Goethe Univ, Pharmazentrum Frankfurt, D-60590 Frankfurt, Germany
关键词
extracellular matrix; nitric oxide; plasminogen activator inhibitor; tissue plasminogen activator; superoxide; reactive oxygen species; hydrogen peroxide; mesangial cells;
D O I
10.1046/j.1523-1755.2002.00087.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. Dysregulated expression of diverse proteases and their specific inhibitors is critical for the increase in extracellular matrix accumulation that accompanies chronic inflammatory and sclerotic processes within the renal mesangium. Within the activating cascade of several proteases, the plasminogen system plays an important role. Methods. We tested for modulatory effects of the nitric oxide (NO) donors S-nitroso-N-acetyl-D,L-penicillamine and DETA-NONOate, and the superoxide-generating system hypoxanthine/xanthine oxidase (HXXO) on the expression and activity of tissue plasminogen activator (tPA) by ELISA and Northern blotting. Results. Interleukin-1 beta (IL-1 beta)-induced tPA and plasminogen activator inhibitor (PAI)-1 mRNA and supernatant tPA antigen were significantly inhibited by both NO donors, which resulted in a net decrease in the IL-1 beta -evoked tPA enzyme activity in the conditioned media. Addition of the NO-synthase inhibitor N-monomethyl L-arginine markedly increased the cytokine-triggered tPA- and PAI-1 mRNA levels. respectively. In contrast, HXXO caused a marked amplification of the IL-1 beta -induced steady-state tPA mRNA level and tPA enzyme activity that was blocked by catalase. Since MnTBAP, a superoxide dismutase mimetic, had no effects on the amplification of mRNA levels, we suggest that H2O2 is the candidate reactive oxygen species (ROS) responsible for the potentiation of IL-1 beta -triggered tPA and PAM expression. Conclusions. The temporal relationship between NO and ROS generation is a critical step in the modulation of tPA and PAI-1 expression in mesangial cells and may account for a dysregulation of matrix turnover during inflammatory processes in the renal mesangium.
引用
收藏
页码:20 / 30
页数:11
相关论文
共 48 条
[1]   LEUKOTRIENES AND REACTIVE OXYGEN SPECIES AS MEDIATORS OF GLOMERULAR INJURY [J].
ARDAILLOU, R ;
BAUD, L ;
SRAER, J .
AMERICAN JOURNAL OF NEPHROLOGY, 1989, 9 :17-22
[2]   TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND ITS INHIBITOR IN HUMAN GLOMERULONEPHRITIS [J].
AYA, N ;
YOSHIOKA, K ;
MURAKAMI, K ;
HINO, S ;
OKADA, K ;
MATSUO, O ;
MAKI, S .
JOURNAL OF PATHOLOGY, 1992, 166 (03) :289-295
[3]  
Beck KF, 1999, J EXP BIOL, V202, P645
[4]   The role of nitric oxide in innate immunity [J].
Bogdan, CT ;
Röllinghoff, M ;
Diefenbach, A .
IMMUNOLOGICAL REVIEWS, 2000, 173 :17-26
[5]  
Cattell V, 1999, SEMIN NEPHROL, V19, P277
[6]   Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice - Role of endothelin [J].
Chatziantoniou, C ;
Boffa, JJ ;
Ardaillou, R ;
Dussaule, JC .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (12) :2780-2789
[7]   PLASMINOGEN ACTIVATORS, TISSUE DEGRADATION, AND CANCER [J].
DANO, K ;
ANDREASEN, PA ;
GRONDAHLHANSEN, J ;
KRISTENSEN, P ;
NIELSEN, LS ;
SKRIVER, L .
ADVANCES IN CANCER RESEARCH, 1985, 44 :139-266
[8]   PROTEINASES AND GLOMERULAR MATRIX TURNOVER [J].
DAVIES, M ;
MARTIN, J ;
THOMAS, GJ ;
LOVETT, DH .
KIDNEY INTERNATIONAL, 1992, 41 (03) :671-678
[9]   THE ROLE OF REACTIVE OXYGEN SPECIES IN ANIMAL-MODELS OF GLOMERULAR-DISEASE [J].
DIAMOND, JR .
AMERICAN JOURNAL OF KIDNEY DISEASES, 1992, 19 (03) :292-300
[10]   Nitric oxide modulates expression of matrix metalloproteinase-9 in rat mesangial cells [J].
Eberhardt, W ;
Beeg, T ;
Beck, KF ;
Walpen, S ;
Gauer, S ;
Böhles, H ;
Pfeilschifter, J .
KIDNEY INTERNATIONAL, 2000, 57 (01) :59-69