Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic β-cells.
Advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) have been linked to the pathogenesis of diabetic complications, such as retinopathy, neuropathy, and nephropathy. AGEs may induce β-cell dysfunction and apoptosis, another complication of diabetes. However, the role of AGE-RAGE interaction in AGE-induced pancreatic β-cell failure has not been fully elucidated. In this study, we investigated whether AGE-RAGE interaction could mediate β-cell failure. We explored the potential mechanisms in insulin secreting (INS-1) cells from a pancreatic β-cell line, as well as primary rat islets. We found that glycated serum (GS) induced apoptosis in pancreatic β-cells in a dose- and time-dependent manner. Treatment with GS increased RAGE protein production in cultured INS-1 cells. GS treatment also decreased bcl-2 gene expression, followed by mitochondrial swelling, increased cytochrome c release, and caspase activation. RAGE antibody and knockdown of RAGE reversed the β-cell apoptosis and bcl-2 expression. Inhibition of RAGE prevented AGE-induced pancreatic β-cell apoptosis, but could not restore the function of glucose stimulated insulin secretion (GSIS) in rat islets. In summary, the results of the present study demonstrate that AGEs are integrally involved in RAGE-mediated apoptosis and impaired GSIS dysfunction in pancreatic β-cells. Inhibition of RAGE can effectively protect β-cells against AGE-induced apoptosis, but cannot reverse islet dysfunction in GSIS.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, China.
Yunxia
Y
Zhu
Tingting
T
Shu
Yan
Y
Lin
Hongdong
H
Wang
Junwei
J
Yang
Yuguang
Y
Shi
Xiao
X
Han
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D019610:Cytoprotection; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044967:Serum
D007328:Insulin; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D005947:Glucose