Zurampic Protects Pancreatic β-Cells from High Uric Acid Induced-Damage by Inhibiting URAT1 and Inactivating the ROS/AMPK/ERK Pathways.

Abstract

BACKGROUND/AIMS:

Zurampic is a US FDA approved drug for treatment of gout. However, the influence of Zurampic on pancreatic β-cells remains unclear. The study aimed to evaluate the effects of Zurampic on high uric acid-induced damage of pancreatic β-cells and the possible underlying mechanisms.

METHODS:

INS-1 cells and primary rat islets were stimulated with Zurampic and the mRNA expression of urate transporter 1 (URAT1) was assessed by qRT-PCR. Cells were stimulated with uric acid or uric acid plus Zurampic, and cell viability, apoptosis and ROS release were measured by MTT and flow cytometry assays. Western blot analysis was performed to evaluate the expressions of active Caspase-3 and phosphorylation of AMPK and ERK. Finally, cells were stimulated with uric acid or uric acid plus Zurampic at low/high level of glucose (2.8/16.7 mM glucose), and the insulin release was assessed by ELISA.

RESULTS:

mRNA expression of URAT1 was decreased by Zurampic in a dose-dependent manner. Uric acid decreased cell viability, promoted cell apoptosis and induced ROS release. Uric acid-induced alterations could be reversed by Zurampic. Activation of Caspase-3 and phosphorylation of AMPK and ERK were enhanced by uric acid, and the enhancements were reversed by Zurampic. Decreased phosphorylation of AMPK and ERK, induced by Zurampic, was further reduced by adding inhibitor of AMPK or ERK. Besides, uric acid inhibited high glucose-induced insulin secretion and the inhibition was rescued by Zurampic.

CONCLUSIONS:

Zurampic has a protective effect on pancreatic β-cells against uric acid induced-damage by inhibiting URAT1 and inactivating the ROS/AMPK/ERK pathway.

• Authors: Ying Xin, Kun Wang, Zhaotong Jia, Tao Xu, Qiang Xu, Chao Zhang, Jia Liu, Rui Chen, Zhongcai Du, Jianjing Sun
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 47 Issue 3 Pg. 1074-1083 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 29843128 (Publication Type: Journal Article, Retracted Publication)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Anion Transport Proteins
• Reactive Oxygen Species
• Slc22a12 protein, rat
• Thioglycolates
• Triazoles
• lesinurad
• Uric Acid
• Extracellular Signal-Regulated MAP Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Anion Transport Proteins (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Insulin-Secreting Cells (metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Rats
• Reactive Oxygen Species (metabolism)
• Thioglycolates (pharmacology)
• Triazoles (pharmacology)
• Uric Acid (metabolism)