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

R. Kodera, K. Shikata, H. U. Kataoka, T. Takatsuka, S. Miyamoto, M. Sasaki, N. Kajitani, S. Nishishita, K. Sarai, D. Hirota, C. Sato, D. Ogawa, H. Makino

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)965-978
Number of pages14
JournalDiabetologia
Volume54
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • Anti-inflammatory effect
  • Diabetic nephropathy
  • Exendin-4
  • GLP-1 receptor agonist
  • Glomerular endothelial cells
  • Intercellular adhesion molecule-1
  • Macrophage
  • Nuclear factor-κB
  • Type 1 diabetic rats

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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