Abstract
To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A-dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho-c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho-c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4-protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / metabolism
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Animals
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Cells, Cultured
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / metabolism*
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Diabetes Mellitus, Experimental / pathology
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Diabetic Nephropathies / prevention & control*
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Endothelium / drug effects
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Endothelium / enzymology
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Endothelium / metabolism*
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Endothelium / pathology
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Exenatide
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Gene Expression Regulation / drug effects
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Glucagon-Like Peptide 1 / antagonists & inhibitors
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Glucagon-Like Peptide 1 / genetics
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Glucagon-Like Peptide 1 / metabolism*
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents / antagonists & inhibitors
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Hypoglycemic Agents / therapeutic use
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / enzymology
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Kidney Glomerulus / metabolism*
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Kidney Glomerulus / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptides / antagonists & inhibitors
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Peptides / therapeutic use
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Peptides / toxicity
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Protein Kinase C / chemistry
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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Protein Kinase C beta
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Proto-Oncogene Proteins c-raf / metabolism
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RNA Interference
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Receptors, Glucagon / antagonists & inhibitors
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Receptors, Glucagon / genetics
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Receptors, Glucagon / metabolism*
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Signal Transduction / drug effects
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Tissue Culture Techniques
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Venoms / therapeutic use
Substances
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Glp1r protein, mouse
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Peptides
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Receptors, Glucagon
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Venoms
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Angiotensin II
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exendin 3
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Glucagon-Like Peptide 1
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Exenatide
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Proto-Oncogene Proteins c-raf
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Protein Kinase C
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Protein Kinase C beta