Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes
- Akira Mima1,
- Junko Hiraoka-Yamomoto1,
- Qian Li1,
- Munehiro Kitada1,
- Chenzhong Li1,
- Pedro Geraldes2,
- Motonobu Matsumoto1,
- Koji Mizutani1,
- Kyoungmin Park1,
- Christopher Cahill1,
- Shin-Ichi Nishikawa3,
- Christian Rask-Madsen1 and
- George L. King1⇓
- 1Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- 2Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada
- 3Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan
- Corresponding author: George L. King, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1824/-/DC1.
- Received December 23, 2011.
- Accepted May 12, 2012.
- © 2012 by the American Diabetes Association.
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