Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways.
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 (3)H-labeled thymidine incorporation and its related signal pathway in primary cultured rabbit renal proximal tubule cells (PTCs). The effects of oxalate on [(3)H]thymidine incorporation, lactate dehydrogenase (LDH) release, Trypan blue exclusion, H(2)O(2) release, activation of mitogen-activated protein kinases (MAPKs), and (3)H-labeled arachidonic acid (AA) release were examined in primary cultured renal PTCs. Oxalate inhibited [(3)H]thymidine incorporation in a time- and dose-dependent manner. However, its analogs did not affect [(3)H]thymidine incorporation. Oxalate (1 mM) significantly increased H(2)O(2) 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 NH(2)-terminal kinase (JNK) activity, not p44/42 MAPK. Oxalate stimulated [(3)H]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 [(3)H]thymidine incorporation and increase of [(3)H]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.
Han
Ho Jae
HJ
Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea 500-757. hjhan@chonnam.ac.kr
Lim
Min Jin
MJ
Lee
Yun Jung
YJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D010070:Oxalates / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010741:Phospholipases A / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D004791:Enzyme Inhibitors; D010070:Oxalates; D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D015232:Dinoprostone