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1 College of Veterinary Medicine, Chonnam National University, Gwangju, Korea, Republic of
2 College of Veterinary Medicine, Seoul National University, Seoul, Korea, Republic of
3 State University of New York at Buffalo, School of Medicine, NY, New York, United States
* To whom correspondence should be addressed. E-mail: hjhan{at}chonnam.ac.kr.
The accumulation of uric acid, an end-product of purine metabolism, is responsible for the many deleterious effects observed in gouty arthritis, including renal injury. Here we present evidence that under conditions of hyperuricemia (> 10-4 M uric acid) [3H]-thymidine incorporation into primary renal proximal tubule cells (PTCs) is inhibited, and we delineate the signaling pathways involved. Elevated uric acid was observed to stimulate the phosphorylation of p38 MAP Kinase (MAPK) and JNK/SAPK. The uric acid induced p38 MAPK phosphorylation was also blocked by H-7 (a PKC inhibitor), indicating that p38 MAPK was a downstream target of PKC. Evidence that cytoplasmic phospholipase A2 (cPLA2) was involved further downstream included, 1) the stimulatory effect of uric acid on [3H]-arachidonic acid (AA) release, 2) the stimulation of AA release in response to uric acid was blocked by the PKC inhibitor H-7 as well as by the p38 MAPK inhibitor SB 203580, and 3) the uric acid-induced inhibition of [3H]-thymidine incorporation was prevented by SB 203580, as well as by the cPLA2 inhibitor AACOCF3, and mepacrine (another PLA2 inhibitor). Evidence of a uric acid-induced activation of NF-
B as well as PLA2 was obtained. Moreover the uric acid induced inhibition of [3H]-thymidine incorporation was also blocked by two NF-B inhibitors PDTC and SN50. However SN 50 did not block the uric acid induced [3H]-AA release. Thus the inhibition of [3H]-thymidine incorporation caused by uric acid can be explained by two distinct mechanisms, the activation of NF-B as well as the activation of PLA2.
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