Hydrogen sulfide mechanism of renal hypertension
硫化氢肾性高血压的机制
基本信息
- 批准号:9091516
- 负责人:
- 金额:$ 63.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): For decades, hydrogen sulfide (H2S) was known only for its neurotoxicity and as an environmental hazard. Recent findings however, suggest that endogenous H2S has a variety of physiological functions and a decrease in production can lead to vascular dysfunction, atherosclerosis and hypertension. This discovery has stimulated further research into its development as a potential therapeutic agent in diseases attributed to diminished H2S synthesis. In chronic kidney disease, low levels of plasma H2S is often associated with a concomitant increase in homocysteine (Hcy), known as hyperhomocysteinemia (HHcy). HHcy is well known to cause vascular dysfunction. The cause and effect relationship of HHcy in renal disease can therefore adversely affect the final outcome. Because Hcy is a precursor of H2S, changes in the H2S metabolism can have a significant impact on HHcy-induced pathology. However, the mechanism by which HHcy causes vascular dysfunction and the role of H2S in renal protection is incompletely understood. In the body, Hcy is metabolized by three enzymes, cystathionine β-synthase (CBS), cystathionine y-lyase (CSE) and 3- mercaptopyruvate sulfurtransferase (3MST) and produce H2S. During HHcy, an impairment in these enzymes leads to deficient H2S production. Our preliminary studies suggest that HHcy results in upregulation of caveolin-1 and homocysteinylation of eNOS thus decreasing NO production. The resulting imbalance in matrix metalloproteinases and their tissue inhibitors of metalloproteinases causes accumulation of extracellular matrix proteins leading to microvascular remodeling, renal dysfunction and hypertension. In this proposal, we hypothesize that H2S offers renal protection from HHcy-induced renal damage by inhibition of caveolin-1 and modulation of eNOS. We will test this hypothesis in vivo and in vitro. Wild type (C57BL/6J) and genetic model of HHcy (CBS+/-) mice will be supplemented without or with H2S. To determine whether HHcy effects are caveolin-1 dependent we will use caveolin-1-/- mice supplemented with high Hcy diet. To ameliorate the HHcy- induced injury, single, double or triple gene delivery system employing CBS, CSE and 3MST enzymes will be used to enhance conversion of Hcy to H2S. In addition to confirming the preliminary findings, further studies will be performed for a deeper understanding into H2S-mediated improvement in renovascular dysfunction caused by pro-fibrotic and pro-inflammatory effects of HHcy. This research is novel because it evaluates gene delivery as a therapeutic option to ameliorate HHcy-induced microvascular remodeling, renal dysfunction and hypertension.
描述(由适用提供):数十年来,硫化氢(H2S)仅以神经毒性和环境危害而闻名。然而,最近的发现表明,内源性H2S具有多种物理功能,生产降低会导致血管功能障碍,动脉粥样硬化和高血压。这一发现刺激了其作为疾病中潜在治疗剂的发展的进一步研究,归因于H2S合成的降低。在慢性肾脏疾病中,低水平的血浆H2S通常与同型半胱氨酸(HCY)伴随的增加有关,称为高肌舒适性半胱氨酸血症(HHCY)。 HHCY众所周知会引起血管功能障碍。因此,HHCY在肾脏疾病中的因果关系可能会对最终结果产生不利影响。由于HCY是H2S的先驱,因此H2S代谢的变化可能会对HCY诱导的病理产生重大影响。但是,HHCY引起血管功能障碍的机制以及H2在肾脏保护中的作用尚不完全了解。在体内,HCY由三种酶,胱磷酸β-合成酶(CBS),胱胱氨酸蛋氨酸蛋白Y-乙醇酸酶(CSE)和3-丙型丙烷硫酸盐硫酸盐硫酸盐转移酶(3MST)代谢,并产生H2S。在HHCY期间,这些酶的损害会导致缺乏。 H2S生产。我们的初步研究表明,HHCY导致小窝蛋白-1的上调和eNOS的同胚化的上调,从而降低了NO产生。基质金属蛋白酶及其金属蛋白酶的组织抑制剂的产生不平衡导致细胞外基质蛋白的积累,导致微血管重塑,肾功能障碍和高血压。在此提案中,我们假设H2S通过抑制可爱素-1和调节ENOS提供了HHCY诱导的肾脏损害的肾脏保护。我们将在体内和体外检验该假设。 HHCY(CBS +/-)小鼠的野生型(C57BL/6J)和遗传模型将在没有H2s或H2S的情况下补充。为了确定hhcy效应是否与可爱素-1相关,我们将使用补充高Hcy饮食的小鼠1-/ - 小鼠。为了改善HHCY诱导的损伤,使用CBS,CSE和3MST酶的单个,双重或三重基因递送系统将用于增强HCY向H2S的转化。除了确认初步发现外,还将进行进一步的研究,以更深入地了解H2S介导的改善HHCY促纤维化和促炎作用引起的肾血管功能障碍的改善。这项研究之所以新颖,是因为它评估基因递送是改善HHCY诱导的微血管重塑,肾功能障碍和高血压的治疗选择。
项目成果
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数据更新时间:2024-06-01
Utpal Sen的其他基金
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衰老过程中急性肾损伤的 miRNA 机制
- 批准号:97525329752532
- 财政年份:2018
- 资助金额:$ 63.56万$ 63.56万
- 项目类别:
miRNA Mechanism of Acute Kidney Injury in Aging
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Hydrogen sulfide mechanism of renal hypertension
硫化氢肾性高血压的机制
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- 财政年份:2015
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Homocysteine and Angiotensin II in Renovascular Remodeling
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Homocysteine and Angiotensin II in Renovascular Remodeling
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Homocysteine and Angiotensin II in Renovascular Remodeling
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Homocysteine and Angiotensin II in Renovascular Remodeling
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Homocysteine & Angiotensin II in Renovascular Remodeling
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