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Complications

Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes

  1. Akira Mima1,
  2. Junko Hiraoka-Yamomoto1,
  3. Qian Li1,
  4. Munehiro Kitada1,
  5. Chenzhong Li1,
  6. Pedro Geraldes2,
  7. Motonobu Matsumoto1,
  8. Koji Mizutani1,
  9. Kyoungmin Park1,
  10. Christopher Cahill1,
  11. Shin-Ichi Nishikawa3,
  12. Christian Rask-Madsen1 and
  13. George L. King1⇓
  1. 1Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
  2. 2Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada
  3. 3Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan
  1. Corresponding author: George L. King, george.king{at}joslin.harvard.edu.
Diabetes 2012 Nov; 61(11): 2967-2979. https://doi.org/10.2337/db11-1824
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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.

Footnotes

  • 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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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November 2012, 61(11)
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Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes
Akira Mima, Junko Hiraoka-Yamomoto, Qian Li, Munehiro Kitada, Chenzhong Li, Pedro Geraldes, Motonobu Matsumoto, Koji Mizutani, Kyoungmin Park, Christopher Cahill, Shin-Ichi Nishikawa, Christian Rask-Madsen, George L. King
Diabetes Nov 2012, 61 (11) 2967-2979; DOI: 10.2337/db11-1824

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Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes
Akira Mima, Junko Hiraoka-Yamomoto, Qian Li, Munehiro Kitada, Chenzhong Li, Pedro Geraldes, Motonobu Matsumoto, Koji Mizutani, Kyoungmin Park, Christopher Cahill, Shin-Ichi Nishikawa, Christian Rask-Madsen, George L. King
Diabetes Nov 2012, 61 (11) 2967-2979; DOI: 10.2337/db11-1824
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