Document Detail


Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kappaB.
MedLine Citation:
PMID:  16985215     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ho Jae Han; Min Jin Lim; Yun Jung Lee; Jang Hern Lee; Il Suk Yang; Mary Taub
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-19
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  292     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-09     Completed Date:  2007-02-12     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F373-81     Citation Subset:  IM    
Affiliation:
Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea. hjhan@chonnam.ac.kr
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonic Acid / metabolism
Biotransformation / drug effects
Blotting, Western
Cell Proliferation / drug effects
Cell Separation
Cell Survival / drug effects
DNA / biosynthesis
Electrophoretic Mobility Shift Assay
Enzyme Activation / drug effects
Kidney Tubules, Proximal / cytology*,  drug effects
L-Lactate Dehydrogenase / metabolism
Male
NF-kappa B / metabolism*
Phospholipases A / metabolism*
Protein Kinase C / metabolism*
Rabbits
Signal Transduction / drug effects*
Thymidine / metabolism
Uric Acid / pharmacology*
p38 Mitogen-Activated Protein Kinases / metabolism*
Chemical
Reg. No./Substance:
0/NF-kappa B; 50-89-5/Thymidine; 506-32-1/Arachidonic Acid; 69-93-2/Uric Acid; 9007-49-2/DNA; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.1.1.-/Phospholipases A

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