Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes

Diabetologia. 2011 Apr;54(4):965-78. doi: 10.1007/s00125-010-2028-x. Epub 2011 Jan 21.


Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose.

Methods: We administered exendin-4 at 10 μg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro.

Results: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells.

Conclusions/interpretation: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Collagen Type IV / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetic Nephropathies / prevention & control
  • Exenatide
  • Fluorescent Antibody Technique
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Male
  • NF-kappa B / metabolism
  • Peptides / pharmacology*
  • Peptides / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology
  • Venoms / pharmacology*
  • Venoms / therapeutic use*


  • Blood Glucose
  • Collagen Type IV
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • NF-kappa B
  • Peptides
  • Receptors, Glucagon
  • Tumor Necrosis Factor-alpha
  • Venoms
  • Intercellular Adhesion Molecule-1
  • Exenatide