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
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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.
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Exendin-4 (3 and 10 μg/kg/day) treatment significantly downregulated the gene expression of CD14, ICAM-1, and TGFβ1 in the renal cortex, prevented glomerular macrophage infiltration in glomeruli, and reduced oxidative stress and inflammation in tubular cells in STZ-induced diabetic animals.
“Exendin-4 (3 and 10 μg/kg/day) treatment significantly downregulated the gene expression of CD14, ICAM-1, and TGFβ1 in the renal cortex, prevented glomerular macrophage infiltration in glomeruli, and reduced oxidative stress and inflammation in tubular cells in STZ-induced diabetic animals [101, 103].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [101]
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Experimental — accuracy not yet measuredThe GLP-1 receptor is expressed in glomerular capillaries and vascular walls of the mouse kidney and in the glomerulus and proximal convoluted tubules of the rat and pig.
“The GLP-1 receptor is expressed in glomerular capillaries and vascular walls of the mouse kidney [14, 101] and in the glomerulus and proximal convoluted tubules of the rat and pig [29, 102].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [101]
The ‘GLP-1R in rat glomeruli’ section demonstrates receptor expression in rat glomeruli, including glomerular endothelial cells. It does not establish expression in proximal convoluted tubules or in pigs; the mouse portion of the sentence is attached to other citations. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn that study, exendin-4 was associated with reduced kidney inflammation and fibrosis.
“Concomitant effects including reduced kidney inflammation and fibrosis were also observed.”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [57]
The Microinflammation in the kidney section reports reduced macrophage infiltration, inflammatory markers, and type IV collagen with exendin-4. However, the Kidney morphology section says no histological interstitial fibrosis was seen in any group, so the study does not establish a reduction in fibrosis itself. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStudies on kidney tissue revealed that exendin-4 suppressed NF-kB activity.
“Studies on kidney tissue revealed that exendin-4 suppressed NF-kB activity.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [39]
Exendin-4 inhibited the generation of the adhesion molecule ICAM-1 in glomerular endothelial cells, and this effect could be blocked by a GLP-1 receptor antagonist.
“For example, exendin-4 inhibited the generation of the adhesion molecule ICAM-1 in these endothelial cells, and this effect could be blocked by a GLP-1 receptor antagonist (57).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [57]
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References 49 · Cited by 394
- 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.
- Affiliations
- Okayama University (JP)
- Corresponding author
- Shikata, K.
- Venue
- Diabetologia
- Published
- 2011-01-21
- Volume
- 54
- Issue
- 4
- Pages
- 965-978
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2090360729
- Cited by
- 394
- References
- 49
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 25 · 2023: 29 · 2022: 34 · 2021: 24 · 2020: 28 · 2019: 23 · 2018: 25 · 2017: 22 · 2016: 32 · 2015: 20 · 2014: 27 · 2013: 33 · 2012: 23
- FWCI
- 22.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, Labour and Welfare
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- GLP-1 receptor agonists, exendin-4, diabetic nephropathy, type 1 diabetes, renal inflammation, albuminuria, glomerular hyperfiltration, macrophage infiltration, ICAM-1, NF-κB activation, oxidative stress, glomerular endothelial cells, mesangial expansion, renal protection
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Animals, Blood Glucose, Cell Line, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fluorescent Antibody Technique, Humans, Male, Peptides, Tumor Necrosis Factor-alpha, Venoms, Blotting, Western, NF-kappa B, Rats, Sprague-Dawley, Receptors, Glucagon, Intercellular Adhesion Molecule-1, Reverse Transcriptase Polymerase Chain Reaction, Collagen Type IV, Cell Line, Tumor, Rats
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