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

• Published in: Diabetologia Vol. 54; no. 4; pp. 965 - 978
• Main Authors: Kodera, R, Shikata, K, Kataoka, H. U, Takatsuka, T, Miyamoto, S, Sasaki, M, Kajitani, N, Nishishita, S, Sarai, K, Hirota, D, Sato, C, Ogawa, D, Makino, H
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.04.2011; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; anti-inflammatory activity; Associated diseases and complications; Biological and medical sciences; Blood Glucose - drug effects; Blotting, Western; Cell Line; Cell Line, Tumor; Collagen Type IV - metabolism; Dentistry; Diabetes; Diabetes Mellitus, Type 1 - drug therapy; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - prevention & control; Diabetic nephropathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exendin-4; Fluorescent Antibody Technique; Glomerular endothelial cells; GLP-1 receptor agonist; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Human Physiology; Humans; Hypertension; Hypothalamus; Injuries of the urinary system. Foreign bodies. Diseases due to physical agents; Intercellular adhesion molecule-1; Intercellular Adhesion Molecule-1 - metabolism; Internal Medicine; Kidneys; Kinases; Macrophage; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; Nuclear factor-κB; Oxidative stress; Peptides; Peptides - pharmacology; Peptides - therapeutic use; Pharmaceutical sciences; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - agonists; Receptors, Glucagon - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Traumas. Diseases due to physical agents; Tumor Necrosis Factor-alpha - pharmacology; Type 1 diabetic rats; Urinary system involvement in other diseases. Miscellaneous; Venoms - pharmacology; Venoms - therapeutic use; Japan; Intercellular adhesion molecule-1; Type 1 diabetic rats; Anti-inflammatory effect; Diabetic nephropathy; GLP-1 receptor agonist; Nuclear factor-κB; Glomerular endothelial cells; Exendin-4; Macrophage; Endocrinopathy; Animal model; Agonist; Endothelial cell; Rat; Autoimmune disease; Glucose; Kidney traumatism; Gastrointestinal hormone; Biological receptor; Kidney disease; Immunopathology; Urinary system disease; Intercellular adhesion molecule 1; Rodentia; Glucagon like peptide 1; Concomitant disease; Vertebrata; Mammalia; Type 1 diabetes; Animal
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-2028-x

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.