Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways
Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways
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DOI：
10.1152/ajpcell.00063.2004
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发表时间：
2004-10-01
影响因子：
5.5
通讯作者：
Lee, YJ
中科院分区：
文献类型：
--
作者：
Han, HJ;Lim, MJ;Lee, YJ
肾近曲小管细胞暴露于草酸盐可能在细胞增殖中起重要作用，但参与这种作用的信号通路尚未阐明。本研究旨在探讨草酸对原代培养的兔肾近端小管细胞（PTC）H-3标记胸苷掺入及其相关信号通路的影响。在原代培养的肾PTCs上观察草酸对[H-3]胸苷掺入、乳酸脱氢酶（LDH）释放、台盼蓝拒染、H2 O2释放、丝裂原活化蛋白激酶（MAPK）活化和H-3标记花生四烯酸（AA）释放的影响。草酸盐以时间和剂量依赖性方式抑制[H-3]胸苷掺入。然而，其类似物不影响[H-3]胸苷掺入。草酸盐（1 mM）显着增加过氧化氢的释放，这是由N-乙酰基-L-半胱氨酸（NAC）和过氧化氢酶（抗氧化剂）阻断。草酸显著增加p38 MAPK和应激活化蛋白激酶（SAPK）/c-Jun氨基末端激酶（JNK）活性，而不增加p44/42 MAPK活性。草酸刺激[H-3] AA的释放和胞质磷脂酶A（2）（cPLA（2））从胞质部分到膜部分的易位。事实上，与对照组相比，草酸盐显著增加了前列腺素E-2（PGE（2））的产生。抗氧化剂（NAC）、p38 MAPK抑制剂（SB-203580）、SAPK/JNK抑制剂（SP-600125）或PLA（2）抑制剂[米帕林和花生四烯酸三氟甲基酮（AACOCF（3））]可阻止草酸盐诱导的[H-3]胸苷掺入抑制和[H-3] AA释放增加，但p44/42 MAPK抑制剂（PD-98059）不能阻止。这些发现表明草酸盐通过氧化应激、p38 MAPK/JNK和cPLA（2）信号通路抑制肾PTC增殖。
Exposure of renal proximal tubule cells to oxalate may play an important role in cell proliferation, but the signaling pathways involved in this effect have not been elucidated. Thus the present study was performed to examine the effect of oxalate on H-3-labeled thymidine incorporation and its related signal pathway in primary cultured rabbit renal proximal tubule cells (PTCs). The effects of oxalate on [H-3] thymidine incorporation, lactate dehydrogenase (LDH) release, Trypan blue exclusion, H2O2 release, activation of mitogen-activated protein kinases (MAPKs), and H-3-labeled arachidonic acid ( AA) release were examined in primary cultured renal PTCs. Oxalate inhibited [H-3] thymidine incorporation in a time- and dose-dependent manner. However, its analogs did not affect [H-3] thymidine incorporation. Oxalate ( 1 mM) significantly increased H2O2 release, which was blocked by N-acetyl-L-cysteine (NAC) and catalase ( antioxidants). Oxalate significantly increased p38 MAPK and stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) activity, not p44/42 MAPK. Oxalate stimulated [H-3] AA release and translocation of cytosolic phospholipase A(2) (cPLA(2)) from the cytosolic fraction to the membrane fraction. Indeed, oxalate significantly increased prostaglandin E-2 (PGE(2)) production compared with control. Oxalate-induced inhibition of [H-3] thymidine incorporation and increase of [H-3] AA release were prevented by antioxidants (NAC), a p38 MAPK inhibitor (SB-203580), a SAPK/JNK inhibitor (SP-600125), or PLA(2) inhibitors [ mepacrine and arachidonyl trifluoromethyl ketone (AACOCF(3))], but not by a p44/42 MAPK inhibitor (PD-98059). These findings suggest that oxalate inhibits renal PTC proliferation via oxidative stress, p38 MAPK/JNK, and cPLA(2) signaling pathways.