A novel compound AB38b attenuates oxidative stress and ECM protein accumulation in kidneys of diabetic mice through modulation of Keap1/Nrf2 signaling.

Abstract

Extracellular matrix (ECM) deposition following reactive oxygen species (ROS) overproduction has a key role in diabetic nephropathy (DN), thus, antioxidant therapy is considered as a promising strategy for treating DN. Here, we investigated the therapeutic effects of AB38b, a novel synthetic α, β-unsaturated ketone compound, on the oxidative stress (OS) and ECM accumulation in type 2 diabetes mice, and tried to clarify the mechanisms underlying the effects in high glucose (HG, 30 mM)-treated mouse glomerular mesangial cells (GMCs). Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration. The diabetic mice were then treated with AB38b (10, 20, 40 mg· kg-1· d-1, ig) or a positive control drug resveratrol (40 mg· kg-1· d-1, ig) for 8 weeks. We showed that administration of AB38b or resveratrol prevented the increases in malondialdehyde level, lactate dehydrogenase release, and laminin and type IV collagen deposition in the diabetic kidney. Simultaneously, AB38b or resveratrol markedly lowered the level of Keap1, accompanied by evident activation of Nrf2 signaling in the diabetic kidney. The underlying mechanisms of antioxidant effect of AB38b were explored in HG-treated mouse GMCs. AB38b (2.5-10 μM) or resveratrol (10 μM) significantly alleviated OS and ECM accumulation in HG-treated GMCs. Furthermore, AB38b or resveratrol treatment effectively activated Nrf2 signaling by inhibiting Keap1 expression without affecting the interaction between Keap1 and Nrf2. Besides, AB38b treatment effectively suppressed the ubiquitination of Nrf2. Taken together, this study demonstrates that AB38b ameliorates experimental DN through antioxidation and modulation of Keap1/Nrf2 signaling pathway.

• Authors: Lei Du, Lei Wang, Bo Wang, Jin Wang, Meng Hao, Yi-Bing Chen, Xi-Zhi Li, Yuan Li, Yan-Fei Jiang, Cheng-Cheng Li, Hao Yang, Xiao-Ke Gu, Xiao-Xing Yin, Qian Lu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 41 Issue 3 Pg. 358-372 (Mar 2020) ISSN: 1745-7254 [Electronic] United States
• PMID: 31645661 (Publication Type: Journal Article)

Chemical References

• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• Ketones
• Morpholines
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Resveratrol

Topics

• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, pathology)
• Diabetic Nephropathies (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Extracellular Matrix (drug effects)
• Kelch-Like ECH-Associated Protein 1 (antagonists & inhibitors, metabolism)
• Ketones (chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Morpholines (chemistry, pharmacology)
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Resveratrol (chemistry, pharmacology)
• Signal Transduction (drug effects)
• Structure-Activity Relationship