title: Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes.
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.
authors: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors: Akira
authors: A
authors: Mima
authors: Junko
authors: J
authors: Hiraoka-Yamomoto
authors: Qian
authors: Q
authors: Li
authors: Munehiro
authors: M
authors: Kitada
authors: Chenzhong
authors: C
authors: Li
authors: Pedro
authors: P
authors: Geraldes
authors: Motonobu
authors: M
authors: Matsumoto
authors: Koji
authors: K
authors: Mizutani
authors: Kyoungmin
authors: K
authors: Park
authors: Christopher
authors: C
authors: Cahill
authors: Shin-Ichi
authors: S
authors: Nishikawa
authors: Christian
authors: C
authors: Rask-Madsen
authors: George L
authors: GL
authors: King
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000037:antagonists & inhibitors / Q000627:therapeutic use / Q000633:toxicity; D011493:Protein Kinase C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014688:Venoms / Q000627:therapeutic use
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000804:Angiotensin II; C066448:exendin 3; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D064546:Protein Kinase C beta