Title:Can Targeting the Incretin Pathway Dampen RAGE-Mediated Events in Diabetic Nephropathy?
Volume: 17
Issue: 11
Author(s): Karly C. Sourris, Henry Yao, George Jerums, Mark E.Cooper, Elif I. Ekinci and Melinda T. Coughlan
Affiliation:
Keywords:
Diabetic nephropathy, dipeptidylpeptidase-4 (DPP4), glucagon like peptide-1, incretin, kidney, receptor for advanced
glycation end products.
Abstract: Diabetic nephropathy is the major cause of end-stage renal disease in Western societies. To
date, interruption of the Renin-Angiotensin System is the most effective intervention for diabetic nephropathy, however
these agents only slow progression of the disease. Thus, there is a major unmet need for new therapeutic targets. Aberrant
activation of the receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic nephropathy
via binding to a variety of ligands and inciting reactive oxygen species (ROS) production, inflammation and fibrosis.
In recent years there have been considerable efforts in the development of effective RAGE antagonists, however, direct
RAGE targeting may be problematic. Glucagon like peptide-1 (GLP-1) is an incretin hormone released by the L-cells
of the small intestine to mediate glucose-dependent insulin release from pancreatic islets. The incretin-based therapies,
GLP-1 receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors, are novel glucose-lowering agents used in type 2
diabetes. However, the extra pancreatic functions of GLP-1 have gained attention, including putative anti-apoptotic and
anti-inflammatory properties. In rodent models of diabetes, incretin-based therapies are renoprotective. Interestingly,
GLP-1 has been shown to interfere with the signalling and expression of RAGE. The current review aims to give an overview
of the interactions between the RAGE and incretin pathways and to discuss the utility of targeting the GLP-1/incretin
pathway in DN. It is possible that indirect targeting of RAGE through GLP-1 agonism will be of clinical benefit to patients
with diabetic nephropathy.
