Increased Unbound Retinol-binding Protein 4 Concentration Induces Apoptosis through Receptor-mediated Signaling

被引：26

作者：

Chen, Chao-Hung ^{[3
]}

Hsieh, Tusty-Jiuan ^{[2
]}

Lin, Kun-Der ^{[1
]}

Lin, Hsing-Yi ^{[1
]}

Lee, Mei-Yueh ^{[1
]}

Hung, Wei-Wen ^{[1
]}

Hsiao, Pi-Jung ^{[1
,2
]}

Shin, Shyi-Jang ^{[1
,2
]}

机构：

[1] Kaohsiung Med Univ, Div Endocrinol & Metab, Kaohsiung Med Univ Hosp, Kaohsiung 80708, Taiwan

[2] Kaohsiung Med Univ, Coll Med, Kaohsiung Med Univ Hosp, Sch Med, Kaohsiung 80708, Taiwan

[3] Kaohsiung Med Univ, Grad Inst Med, Kaohsiung Med Univ Hosp, Kaohsiung 80708, Taiwan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 13期

关键词：

TYPE-2; DIABETIC-PATIENTS; VITAMIN-A; INSULIN-RESISTANCE; SERUM-LEVELS; RETINOL-BINDING-PROTEIN-4; PATHWAYS; KIDNEY; PLASMA; ACID; HOMEOSTASIS;

D O I：

10.1074/jbc.M111.301721

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The increase of apo-/holo-retinol-binding protein 4 (RBP4) concentrations has been found in subjects with renal dysfunction and even in diabetic patients with microalbuminuria. Holo-RBP4 is recognized to possess cytoprotective function. Therefore, we supposed that the relative increase in apo-RBP4 might induce cell damage. In this study, we investigated the signal transduction that activated apoptosis in response to the increase of apo-/holo-RBP4 concentration. We found that increase of apo-/holo-RBP4 concentration ratio delayed the displacement of RBP4 with "stimulated by retinoic acid 6 '' (STRA6), enhanced Janus kinase 2 (JAK2)/STAT5 cascade, up-regulated adenylate cyclase 6 (AC6), increased cAMP, enhanced JNK1/p38 cascade, suppressed CRBP-I/RAR alpha (cellular retinol-binding protein/retinoic acid receptor alpha) expression, and led to apoptosis in HK-2 and human umbilical vein endothelial cells. Furthermore, STRA6, JAK2, STAT5, JNK1, or p38 siRNA and cAMP-PKA inhibitor reversed the repression of CRBP-I/RAR alpha and apoptosis in apo-RBP4 stimulation. In conclusion, this study indicates that the increase of apo-/holo-RBP4 concentration may influence STRA6 signaling, finally causing apoptosis.

引用

页码：9694 / 9707

页数：14

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