Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic
nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric
oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like
peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells.
However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined
the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression
of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates
ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic
rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1
analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated
whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced
diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS,
and ADMA generation in tubular cells, which were blocked by small-interfering RNAs
raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage,
Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine
and albumin; and improved histopathologic changes of the kidney in diabetic rats.
Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated
ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation,
thereby protecting against the development and progression of diabetic nephropathy.
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier
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