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GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases
Open accessAbstract
Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2'-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.
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“Liraglutide inhibited NOX4 enzymatic activity, and this effect could be blocked by incubation with a protein kinase inhibitor or an adenylate cyclase inhibitor (62).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [62]
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“Indeed, early preclinical studies demonstrated attenuation of renal TGF-β expression in association with reduced expression of collagens within the kidney after GLP-1 receptor agonist therapy (62).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [62]
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Metadata
- Authors
- Hendarto, H., Inoguchi, T., Maeda, Y., Ikeda, N., Zheng, J., Takei, R., Yokomizo, H., Hirata, E., Sonoda, N., & Takayanagi, R.
- Affiliations
- Kyushu University (JP)
- Corresponding author
- Inoguchi, Toyoshi
- ORCID
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 61
- Issue
- 10
- Pages
- 1422-1434
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W1983883248
- Cited by
- 232
- References
- 43
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 20 · 2023: 16 · 2022: 8 · 2021: 17 · 2020: 21 · 2019: 21 · 2018: 18 · 2017: 15 · 2016: 16 · 2015: 19 · 2014: 14 · 2013: 18 · 2012: 4
- FWCI
- 13.96
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Universitas Islam Negeri Syarif Hidayatullah Institutional Repository (Universitas Islam Negeri Syarif Hidayatullah Jakarta) (submittedVersion, cc-by-nc)
- Funders
- Japan Society for the Promotion of Science (23390247)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- liraglutide, GLP-1 analogues, diabetic nephropathy, oxidative stress, albuminuria, protein kinase A, NADPH oxidase, type 1 diabetes, streptozotocin-induced diabetes, renal mesangial cells, superoxide production, TGF-beta, fibronectin, Epac2, renal fibrosis
- MeSH terms
- Liraglutide, Adenine, Albuminuria, Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Humans, Isoquinolines, Kidney, Male, Multienzyme Complexes, NADH, NADPH Oxidoreductases, Streptozocin, Sulfonamides, Rats, Wistar, Cyclic AMP-Dependent Protein Kinases, Oxidative Stress, Rats, Glucagon-Like Peptide 1
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