title: Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kappaB.
abstract: 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) [(3)H]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 A(2) (cPLA(2)) was involved further downstream included 1) the stimulatory effect of uric acid on [(3)H]-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 [(3)H]thymidine incorporation was prevented by SB 203580, as well as by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone, and mepacrine (another PLA(2) inhibitor). Evidence of a uric acid-induced activation of NF-kappaB as well as PLA(2) was obtained. Moreover the uric acid-induced inhibition of [(3)H]thymidine incorporation was also blocked by two NF-kappaB inhibitors, pyrrolidine dithiocarbamate and SN 50. However, SN 50 did not block the uric acid induced [(3)H]AA release. Thus the inhibition of [(3)H]thymidine incorporation caused by uric acid can be explained by two distinct mechanisms, the activation of NF-kappaB as well as the activation of PLA(2).
authors.affiliation: Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea. hjhan@chonnam.ac.kr
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Lim
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jang Hern
authors.initials: JH
authors.lastname: Lee
authors.forename: Il Suk
authors.initials: IS
authors.lastname: Yang
authors.forename: Mary
authors.initials: M
authors.lastname: Taub
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014527:Uric Acid; D016718:Arachidonic Acid; D004247:DNA; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D013936:Thymidine