全反式维甲酸和丙戊酸:治疗肾病综合征的组合方法

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Rini Varghese, Anuradha Majumdar
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引用次数: 0

摘要

大量蛋白尿、水肿、低蛋白血症和高脂血症是肾病综合征(NS)的特征。最近,人们发现了肾脏疾病的表观遗传途径。本研究假设将全反式维甲酸(ATRA)和丙戊酸(VPA)这两种表观遗传药物联合使用,作为一种前瞻性治疗方法,以减轻与NS相关的肾小球硬化、纤维化和肾功能参数的增加,同时减轻炎症反应并改善线粒体的整体健康。为了诱导 NS,雌性 Sprague Dawley 大鼠静脉注射多柔比星(8.5 毫克/千克,n = 6)。28 天后,给大鼠口服 ATRA 和 VPA,剂量分别为 5 毫克/千克(n = 6)和 200 毫克/千克(n = 6)的芝麻油和生理盐水。泼尼松龙(3 毫克/千克,生理盐水;n = 6)作为标准用药。经过 21 天的治疗后,大鼠被处死,并在处死前 24 小时采集尿液样本。收集血液样本并提取肾脏样本用于进一步分析。与阳性对照组相比,ATRA 和 VPA 组合组的肾功能参数(蛋白尿、尿素氮、白蛋白、肌酐)、组织再造和纤维化标志物水平(TGF-β、MMP2 活性)、胆固醇和甘油三酯水平均有显著改善。组织病理学分析显示,炎症、肾小球硬化和纤维化有所减轻。通过 ELISA 法测定的炎症标志物,即 TNF-α、IL-1β、IL-6 和 NF-κB,均出现下调。通过 RT-qPCR 分析的线粒体生物生成标志物(即 PGC-1α、TFAM、NRF1、Nrf2、PPAR-γ、KEAP-1)上调,因此与阳性对照组和标准组相比,联合组的情况有显著改善。这项研究总体上为治疗 NS 提供了一种新方法,我们的发现必将推动更多的临床前和临床探索研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

All-trans-retinoic acid and valproic acid: A combinatorial approach for the treatment of nephrotic syndrome

All-trans-retinoic acid and valproic acid: A combinatorial approach for the treatment of nephrotic syndrome

Massive proteinuria, oedema, hypoalbuminemia, and hyperlipidemia are the hallmarks of nephrotic syndrome (NS). Recently, epigenetic pathways in renal diseases have been identified. The present work hypothesizes using the combination of two epigenetic drugs all-trans retinoic acid (ATRA) and valproic acid (VPA) as a prospective treatment method to lessen NS-related glomerulosclerosis, fibrosis, and increased renal function parameters along with attenuating inflammation and improving overall mitochondrial health. To induce NS, doxorubicin (8.5 mg/kg, n = 6) was injected intravenously into female Sprague Dawley rats. After 28 days, ATRA and VPA were orally administered to the rats, alone and in combination at a dose of 5 mg/kg (n = 6) and 200 mg/kg (n = 6) in sesame oil and saline, respectively. Prednisolone (3 mg/kg in saline; n = 6) was used as standard. Following 21-day treatment period, the rats were sacrificed prior to which 24 hrs urine samples were obtained. Blood samples were collected and kidneys were extracted for further analyses. Renal function parameters (proteinuria, BUN, albumin, creatinine), levels of tissue reengineering and fibrosis markers (TGF-β, MMP2 activity), cholesterol and triglyceride levels were significantly improved in the ATRA and VPA combination group as compared to positive control group. Histopathological analyses revealed a reduction in inflammation, glomerulosclerosis and fibrosis. The inflammatory markers, namely TNF-α, IL-1β, IL-6, NF-κB, determined by ELISA were downregulated. Mitochondrial biogenesis markers viz. PGC-1α, TFAM, NRF1, Nrf2, PPAR-γ, KEAP-1, analysed by RT-qPCR were upregulated thereby showing a significant improvement in the combination group as compared to positive control and standard group. The study overall contributes to a novel approach to treating NS and our findings will surely drive additional exploratory preclinical and clinical studies.

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来源期刊
Current Research in Biotechnology
Current Research in Biotechnology Biochemistry, Genetics and Molecular Biology-Biotechnology
CiteScore
6.70
自引率
3.60%
发文量
50
审稿时长
38 days
期刊介绍: Current Research in Biotechnology (CRBIOT) is a new primary research, gold open access journal from Elsevier. CRBIOT publishes original papers, reviews, and short communications (including viewpoints and perspectives) resulting from research in biotechnology and biotech-associated disciplines. Current Research in Biotechnology is a peer-reviewed gold open access (OA) journal and upon acceptance all articles are permanently and freely available. It is a companion to the highly regarded review journal Current Opinion in Biotechnology (2018 CiteScore 8.450) and is part of the Current Opinion and Research (CO+RE) suite of journals. All CO+RE journals leverage the Current Opinion legacy-of editorial excellence, high-impact, and global reach-to ensure they are a widely read resource that is integral to scientists' workflow.
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