| First Author | Mima A | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 11 | Pages | 2967-79 |
| PubMed ID | 22826029 | Mgi Jnum | J:208511 |
| Mgi Id | MGI:5563630 | Doi | 10.2337/db11-1824 |
| Citation | Mima A, et al. (2012) Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCbeta activation in diabetes. Diabetes 61(11):2967-79 |
| abstractText | 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)beta2 in endothelial cells (EC-PKCbeta2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCbeta 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-PKCbeta2Tg mice exhibited decreased GLP-1R expression and increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCbeta2Tg 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 PKCbeta activation and the increased degradation of GLP-1R in the glomerular endothelial cells. |
