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.

The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. George L. King, MD, of the Section of Vascular Cell Biology and Complications, Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA, received the prestigious award at the American Diabetes Association’s 75th Scientific Sessions, 5–9 June 2015, in Boston, MA. He presented the Edwin Bierman Award Lecture, “Selective Insulin Resistance and the Development of Cardiovascular Disease in Diabetes,” on Sunday, 7 June 2015. This review is focused on the factors and potential mechanisms that are causing various cardiovascular pathologies. In diabetes, insulin’s actions on the endothelium and other vascular cells have significant influence on systemic metabolisms and the development of cardiovascular pathologies. Our studies showed that insulin receptors on the endothelium are important for insulin transport across the endothelial barrier and mediate insulin’s actions in muscle, heart, fat, and the brain. Insulin actions on the vascular cells are mediated by two pathways involving the actions of either IRS/PI3K/Akt or Grb/Shc/MAPK. Insulin’s activation of IRS/PI3K/Akt results in mostly antiatherogenic actions, as this pathway induces activation of eNOS, the expressions of HO-1 and VEGF, and the reduction of VCAM-1. In contrast, insulin’s activation of the Grb/Shc/MAPK pathway mediates the expressions of ET-1 and PAI-1 and migration and proliferation of contractile cells, which have proatherogenic actions. Elevated levels of glucose, free fatty acids, and inflammatory cytokines due to diabetes and insulin resistance selectively inhibit insulin’s antiatherogenic actions via the IRS/PI3K/Akt pathway. This review provides evidence to support the importance of insulin actions in preventing cardiovascular pathology that can be selectively inhibited via the IRS/PI3K/Akt cascade in diabetes.

Wnt signaling is known to regulate multiple processes including angiogenesis, inflammation, and fibrosis. Here, we identified a novel inhibitor of the Wnt pathway, pigment epithelium-derived factor (PEDF), a multifunctional serine proteinase inhibitor. Both overexpression of PEDF in transgenic mice and administration of PEDF protein attenuated Wnt signaling induced by retinal ischemia. Furthermore, PEDF knockdown by small interfering RNA (siRNA) and PEDF knockout in PEDF ؊/؊ mice induced activation of Wnt signaling. PEDF bound to LRP6, a Wnt coreceptor, with high affinity (K d [dissociation constant] of 3.7 nM) and blocked the Wnt signaling induced by Wnt ligand. The physical interaction of PEDF with LRP6 was confirmed by a coprecipitation assay, which showed that PEDF bound to LRP6 at the E1E2 domain. In addition, binding of PEDF to LRP6 blocked Wnt ligand-induced LRP6-Frizzled receptor dimerization, an essential step in Wnt signaling. These results suggest that PEDF is an endogenous antagonist of LRP6, and blocking Wnt signaling may represent a novel mechanism for its protective effects against diabetic retinopathy.