Gentisic acid protects against diabetic nephropathy in Nicotinamide-Streptozotocin administered male mice by attenuating oxidative stress and inflammation: The role of miR-200a/Keap1/Nrf2 pathway, renin-angiotensin system (RAS) and NF-кB.

Abstract

Oxidative stress and inflammation play a pivotal role in the pathogenesis of diabetic nephropathy (DN). Local renin-angiotensin systems (RAS) contribute to the pathogenesis and progression of DN by exacerbating oxidative stress and inflammation.Gentisic acid (GA), a phenolic compound and also a metabolite of aspirin, is reported to possess antioxidant and anti-inflammatory properties. However, the protective effects of GA against DN remain to be elucidated. Nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) were used to induce diabetes in male mice. Oral administration of GA once daily for 2 weeks (100 mg/kg) ameliorated diabetes-induced renal injury by reducing plasma creatinine, urea, blood urea nitrogen, and urinary albuminuria levels. Diabetic mice showed a significant increase in total oxidant status and malondialdehyde, along with decreased catalase, superoxide dismutase, and glutathione peroxidase in the kidney tissue, which was ameliorated in the GA-treated mice. Histopathological analysis showed that GA treatment reduced diabetes-induced renal injury. Furthermore, GA treatment was associated with the downregulation of miR-125b, nuclear factor kappa beta (NF-кB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and upregulation of interleukin-10 (IL-10), miR-200a, and nuclear factor erythroid 2-related factor 2 (Nrf2) in the renal tissue. GA treatment also downregulated angiotensin-converting enzyme 1 (ACE1), angiotensin II receptor 1 (AT1R), and NADPH oxidase 2 (NOX 2) and upregulated angiotensin-converting enzyme 2 (ACE2). In conclusion, the ameliorative effects of GA against DN may be attributed to its powerful antioxidant and anti-inflammatory properties through the downregulation of NF-кB, upregulation of Nrf2, and modulation of RAS in renal tissue.

• Authors: Reza Noei Razliqi, Akram Ahangarpour, Seyyed Ali Mard, Layasadat Khorsandi
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 380 Pg. 110507 (Aug 01 2023) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 37120126 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• NF-kappa B
• Streptozocin
• NF-E2-Related Factor 2
• 2,5-dihydroxybenzoic acid
• Antioxidants
• Niacinamide
• Kelch-Like ECH-Associated Protein 1
• Anti-Inflammatory Agents
• MicroRNAs
• Angiotensins
• Keap1 protein, mouse

Topics

• Mice
• Male
• Animals
• Diabetic Nephropathies (pathology)
• NF-kappa B (metabolism)
• Streptozocin (toxicity)
• Renin-Angiotensin System
• NF-E2-Related Factor 2 (metabolism)
• Antioxidants (metabolism)
• Niacinamide (pharmacology, therapeutic use)
• Diabetes Mellitus, Experimental (complications, drug therapy, metabolism)
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Kidney
• Oxidative Stress
• Inflammation (metabolism)
• Anti-Inflammatory Agents (pharmacology, therapeutic use, metabolism)
• MicroRNAs (metabolism)
• Angiotensins (metabolism, pharmacology, therapeutic use)