Synergistic Renoprotective Effect of Melatonin and Zileuton by Inhibition of Ferroptosis via the AKT/mTOR/NRF2 Signaling in Kidney Injury and Fibrosis.

IF 3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Biomolecules & Therapeutics Pub Date : 2023-11-01 Epub Date: 2023-05-15 DOI:10.4062/biomolther.2023.062
Kyung Hee Jung, Sang Eun Kim, Han Gyeol Go, Yun Ji Lee, Min Seok Park, Soyeon Ko, Beom Seok Han, Young-Chan Yoon, Ye Jin Cho, Pureunchowon Lee, Sang-Ho Lee, Kipyo Kim, Soon-Sun Hong
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引用次数: 3

Abstract

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

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褪黑激素和Zileuton通过AKT/mTOR/NRF2信号抑制肾损伤和纤维化中的脱铁作用而发挥协同肾脏保护作用。
根据最近的证据,脱铁性贫血是肾损伤和纤维化发病机制中的一个主要细胞死亡机制。尽管经典的脱铁症抑制剂具有肾脏保护作用,但针对肾脏脱铁症的治疗方法仍然有限。在这项研究中,我们评估了褪黑素和齐留顿作为一种新的治疗策略对脱铁性贫血介导的肾损伤和纤维化的肾脏保护作用。首先,我们在肾小管上皮细胞HK-2和HKC-8中鉴定了RSL3诱导的脱铁性贫血。褪黑素和齐留顿联合应用可协同减轻RSL3诱导的脂质过氧化和细胞死亡。联合治疗显著下调脱铁相关蛋白4-HNE和HO-1的表达,并上调GPX4的表达。除了NRF2在肾小管上皮细胞中的表达水平外,p-AKT和p-mTOR的表达水平也增加。当对单侧输尿管梗阻(UUO)小鼠模型给予褪黑素(20 mg/kg)和齐留顿(20 g/kg)时,该组合通过降低促纤维化标志物(如α-SMA和纤连蛋白)的表达,显著减少了肾小管损伤和纤维化。更重要的是,该组合改善了UUO小鼠中4-HNE水平的增加并降低了GPX4的表达。总的来说,褪黑素和齐留顿的组合被发现通过上调AKT/mTOR/NRF2信号通路有效改善脱铁性贫血相关的肾损伤,这表明了一种很有前途的治疗策略,可以预防脱铁性肾病介导的肾损伤和纤维化。
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来源期刊
CiteScore
6.60
自引率
8.10%
发文量
72
审稿时长
6-12 weeks
期刊介绍: Biomolecules & Therapeutics (Biomolecules & Therapeutics) (Print ISSN 1976-9148, Online ISSN 2005-4483) is an international, peer-reviewed, open access journal that covers pharmacological and toxicological fields related to bioactive molecules and therapeutics. It was launched in 1993 as "The Journal of Applied Pharmacology (ISSN 1225-6110)", and renamed "Biomolecules & Therapeutics" (Biomol Ther: abbreviated form) in 2008 (Volume 16, No. 1). It is published bimonthly in January, March, May, July, September and November. All manuscripts should be creative, informative, and contribute to the development of new drugs. Articles in the following categories are published: review articles and research articles.
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