Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCß
activation in diabetes.
Authors Mima A, Hiraoka-Yamomoto J, Li Q, Kitada M, Li C, Geraldes P, Matsumoto M,
Mizutani K, Park K, Cahill C, Nishikawa S, Rask-Madsen C, King GL
Submitted By Christian Rask-Madsen on 3/7/2013
Status Published
Journal Diabetes
Year 2012
Date Published 11/1/2012
Volume : Pages 61 : 2967 - 2979
PubMed Reference 22826029
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)ß2 in endothelial
cells (EC-PKCß2Tg) were established. Ang II and GLP-1 actions in glomerular
endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCß
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-PKCß2Tg mice exhibited decreased GLP-1R expression and
increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic
EC-PKCß2Tg 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 PKCß activation and the
increased degradation of GLP-1R in the glomerular endothelial cells.


Investigators with authorship
NameInstitution
Christian Rask-MadsenJoslin Diabetes Center - Boston

Complications