Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-B

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 MAPK phosphorylation. 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]-labeled 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 arachidonyl trifluoromethyl ketone, 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, pyrrolidine dithiocarbamate and SN 50. 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.This work was supported by the Research Project on the Production of Bio-organs (no. 200503010301), Ministry of Agriculture and Forestry, Republic of Korea, and a graduate fellowship provided by the Ministry of Education and Human Resources Development through the Brain Korea 21 project, Republic of Korea