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Am J Physiol Cell Physiol (June 30, 2004). doi:10.1152/ajpcell.00063.2004
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Submitted on February 2, 2004
Accepted on June 2, 2004

Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways

Ho Jae Han1*, Min Jin Lim1, Yun Jung Lee1, and

1 Associate Professor of Department of Physiology, College of Veterinary Medicine, Gwangju, Chonnam National University, Korea, Republic of

* To whom correspondence should be addressed. E-mail: hjhan{at}chonnam.ac.kr.

Exposure of oxalate to renal proximal tubule cells may play an important role in the 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 [3H]-thymidine incorporation and its related signal pathway in primary cultured rabbit renal proximal tubule cells (PTCs). The effects of oxalate on [3H]-thymidine incorporation, LDH release, trypan blue exclusion, H2O2 release, activation of mitogen activated protein kinases (MAPKs), and [3H]-arachidonic acid (AA) release were examined in the primary cultured renal PTCs. Oxalate inhibited [3H]-thymidine incorporation in a time- and dose-dependent manner. However, its analogues did not affect in [3H]-thymidine incorporation. Oxalate (1 mM) significantly increased H2O2 release, which was blocked by N-acetylcysteine (NAC) and catalase (antioxidants). Oxalate significantly increased the p38 MAPK and stress activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) activity, not p44/42 MAPK. Oxalate stimulated [3H]-AA release and translocation of cPLA2 from cytosolic fraction to membrane fraction. Indeed, oxalate significantly increased prostaglandin E2 production compared to control. Oxalate-induced inhibition of [3H]-thymidine incorporation and increase of [3H]-AA release were prevented by antioxidants (NAC), a p38 MAPK inhibitor (SB 203580), a SAPK/JNK inhibitor (SP 600125), or phospholipase A2 inhibitors (mepacrine and AACOCF3), 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 cPLA2 signaling pathways.




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