title: Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells.
abstract: Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic β cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic β cell function. Under high uric acid condition, proliferation of pancreatic β cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK). Pharmacological inhibition of ERK activation rescued β cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. We also investigated the transportation channel for uric acid into pancreatic β cells. While major urate transporter URAT1 is not expressed in β cells, organic anion transporter (OAT) inhibitor successfully blocked the activation of ERK by uric acid. Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic β cells by activating the AMPK and ERK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic β cells.
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yongneng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Youfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Weijie
authors.initials: W
authors.lastname: Cheng
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Bozhi
authors.initials: B
authors.lastname: Cai
authors.forename: Tianliang
authors.initials: T
authors.lastname: Huang
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Xubin
authors.initials: X
authors.lastname: Jing
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Jidong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D033461:Hyperuricemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D027321:Anion Transport Proteins; D007328:Insulin; C554079:Slc22a12 protein, rat; D014527:Uric Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D000263:Adenylate Kinase; D005947:Glucose