Mima, AkiraHiraoka-Yamomoto, JunkoLi, QianKitada, MunehiroLi, ChenzhongGeraldes, PedroMatsumoto, MotonobuMizutani, KojiPark, KyoungminCahill, ChristopherNishikawa, Shin-IchiRask-Madsen, ChristianKing, George2014-03-112012Mima, A., J. Hiraoka-Yamomoto, Q. Li, M. Kitada, C. Li, P. Geraldes, M. Matsumoto, et al. 2012. “Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKCβ Activation in Diabetes.” Diabetes 61 (11): 2967-2979. doi:10.2337/db11-1824. http://dx.doi.org/10.2337/db11-1824.0012-1797http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879125To 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.en-USJournal Article2014-03-1110.2337/db11-1824