Nobiletin Alleviates Ferroptosis-Associated Renal Injury, Inflammation, and Fibrosis in a Unilateral Ureteral Obstruction Mouse Model

Abstract

Nobiletin (Nob), a critical active flavonoid of citrus fruits, has received attention for its superior physical functions, which have shown to improve the progression of diseases. Chronic kidney disease (CKD) is recognized as a global health problem, and its mortality and morbidity rates are worsened with an increased risk of accompanying disorders. In this study, we aimed to elucidate whether Nob treatment ameliorates kidney fibrosis and also to identify the potential signaling networks in a unilateral ureteral obstructive (UUO) mouse model, which was used to mimic the progression of CKD. Six-week-old C57BL/6J mice were orally treated with 50 mg/kg of Nob for 14 constitutive days after UUO surgery. We found that the administration of Nob diminished kidney fibrosis and the expression of EMT markers, ameliorated oxidative stress and ferroptosis-associated injury, and mitigated the inflammatory response in the kidneys of UUO mice. Our results suggested that Nob treatment has antiferroptosis, anti-inflammatory, and antifibrotic effects, improving the progression of CKD in UUO mice. Nob may serve as a potential therapeutic candidate for the improvement of progressive CKD in further studies.

Sulforaphane Protects against Unilateral Ureteral Obstruction-Induced Renal Damage in Rats by Alleviating Mitochondrial and Lipid Metabolism Impairment

“…Inconsistency in these results might be attributed to the fact that the antibody cocktail (OXPHOS) employed to identify CII protein levels detects the succinate dehydrogenase (SDH) B subunit, the most labile protein used for this antibody. This protein contains three iron-sulfur (Fe-S) clusters, making the SDH8 protein more sensitive to oxidative damage, which is found in UUO [ 14 , 61 ]. Moreover, the CII is composed of three additional subunits that enhance its activity: SDHA, SDHC, and SDHD, which do not have Fe-S clusters [ 62 ].…”

Ferroptosis and Its Role in Chronic Diseases

“…Resveratrol nanoparticles can repress erastin-induced ferroptosis in HT22 mouse hippocampal cells [226], and also inhibits acrolein-induced ferroptosis and insulin secretion disorder via the ER-stress-related PERK pathway in mouse pancreatic β cells [227]. Nobiletin, a critical active flavonoid in citrus fruits, was found to reduce ferroptosis-related renal injury, inflammation, and fibrosis in a unilateral ureteral obstruction mouse model [228]. Nobiletin triggers the ferroptosis of human skin melanoma cells via the GSK3β-mediated Keap1/Nrf2/HO-1 signaling pathway [229].…”

Potential Therapeutic Strategies for Renal Fibrosis: Cordyceps and Related Products

“…Oxidative stress occurs when the balance between ROS and reactive nitrogen species and the antioxidant defense system is disrupted, that is, when the production of pro-oxidants or ROS exceeds the endogenous antioxidant capacity (Sies et al, 2017). It has been shown that oxidative stress promotes the progression of RF (Aranda-Rivera et al, 2021); if oxidative stress is suppressed, RF can be attenuated (Liao et al, 2022;Lo et al, 2022). Antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px), protect cells from damage caused by oxygen free radicals.…”