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- Title
Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes.
- Authors
Mima, Akira; Hiraoka-Yamomoto, Junko; Li, Qian; Kitada, Munehiro; Li, Chenzhong; Geraldes, Pedro; Matsumoto, Motonobu; Mizutani, Koji; Park, Kyoungmin; Cahill, Christopher; Nishikawa, Shin-Ichi; Rask-Madsen, Christian; King, George L
- 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
Diabetes, 2012, Vol 61, Issue 11, p2967
- ISSN
1939-327X
- Publication type
Journal Article
- DOI
10.2337/db11-1824