Abstract
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/RARα (cellular retinol-binding protein/retinoic acid receptor α) 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/RARα 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / genetics
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Adenylyl Cyclases / metabolism
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Apoptosis / physiology*
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Cell Line
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Cyclic AMP / genetics
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Cyclic AMP / metabolism
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Diabetes Complications / genetics
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Diabetes Complications / metabolism
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Humans
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Kidney Diseases / genetics
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Kidney Diseases / metabolism
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MAP Kinase Signaling System / physiology*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / metabolism
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Proteinuria / genetics
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Proteinuria / metabolism
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor alpha
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Retinol-Binding Proteins, Plasma / genetics
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Retinol-Binding Proteins, Plasma / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Up-Regulation / physiology
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Membrane Proteins
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RARA protein, human
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RBP4 protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Retinol-Binding Proteins, Plasma
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STAT5 Transcription Factor
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STRA6 protein, human
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Cyclic AMP
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JAK2 protein, human
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Janus Kinase 2
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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Adenylyl Cyclases
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adenylyl cyclase 6