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Hydrogen sulfide mechanism of renal hypertension

硫化氢肾性高血压的机制

基本信息

批准号：
8840391
负责人：
Utpal Sen
金额：
$ 65.34万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
https://reporter.nih.gov/project-details/8840391
关键词：
3-Mercaptopyruvate sulfurtransferase Affect Amino Acids Angiography Antihypertensive Agents Antioxidants Atherosclerosis Blood Pressure Blood Vessels Blood capillaries Cells Chemicals Chronic Kidney Failure Co-Immunoprecipitations Collagen Connexins Cystathionine Cystathionine beta-Synthase Development Diet Disease Endothelial Cells Environmental Hazards Enzymes Extracellular Matrix Extracellular Matrix Proteins Fibrosis Functional disorder Future Gap Junctions Gelatinase A Gelatinases Gene Delivery Genes Genetic Models Glomerular Filtration Rate Goals Homocysteine Homocystine Hydrogen Sulfide Hyperhomocysteinemia Hypertension Impairment In Vitro Inflammatory Injury Interstitial Collagenase Investigation Kidney Kidney Diseases Knowledge Lead Lyase Mass Spectrum Analysis Matrilysin Matrix Metalloproteinases Measures Mediating Messenger RNA Metabolism Methods Molecular Mus Nitric Oxide Outcome Outcomes Research Oxidative Stress Pathology Perfusion Physiological Plasma Process Production Renal Hypertension Renal function Renovascular Hypertension Reporting Research Reverse Transcriptase Polymerase Chain Reaction Roentgen Rays Role Staining method Stains Structure Sulfhydryl Compounds Supplementation Testing Therapeutic Therapeutic Agents Tissue Inhibitor of Metalloproteinases Tissues Up-Regulation Vascular Diseases Vascular remodeling Western Blotting blood pressure regulation capillary caveolin 1 collagenase connexin 37 density gene delivery system human NOS3 protein in vivo insight kidney vascular structure neurotoxicity novel prevent public health relevance

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（由申请人提供）：几十年来，人们只知道硫化氢 (H2S) 具有神经毒性和环境危害。然而，最近的研究结果表明，内源性 H2S 具有多种生理功能，生成量的减少可能导致血管功能障碍、动脉粥样硬化和高血压。这一发现刺激了对其开发的进一步研究，将其作为治疗因 H2S 合成减少引起的疾病的潜在治疗剂。在慢性肾脏疾病中，血浆 H2S 水平低通常与同型半胱氨酸 (Hcy) 增加相关，称为高同型半胱氨酸血症 (HHcy)。众所周知，HHcy 会导致血管功能障碍。因此，HHcy 在肾脏疾病中的因果关系会对最终结果产生不利影响。由于 Hcy 是 H2S 的前体，因此 H2S 代谢的变化会对 HHcy 诱导的病理产生重大影响。然而，HHcy引起血管功能障碍的机制以及H2S在肾脏保护中的作用尚不完全清楚。在体内，Hcy通过三种酶：胱硫醚β-合酶（CBS）、胱硫醚γ-裂解酶（CSE）和3-巯基丙酮酸硫转移酶（3MST）代谢并产生H2S。在 HHcy 期间，这些酶的损伤会导致 H2S 产生不足。我们的初步研究表明，HHcy 导致 Caveolin-1 的上调和 eNOS 的同型半胱氨酸化，从而减少 NO 的产生。由此产生的基质金属蛋白酶及其金属蛋白酶组织抑制剂的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。在此提议中，我们假设 H2S 通过抑制 Caveolin-1 和调节 eNOS 来保护肾脏免受 HHcy 诱导的肾损伤。我们将在体内和体外测试这个假设。野生型 (C57BL/6J) 和 HHcy (CBS+/-) 小鼠遗传模型将补充不添加或添加 H2S。为了确定 HHcy 效应是否依赖 Caveolin-1，我们将使用补充高 Hcy 饮食的 Caveolin-1-/- 小鼠。为了改善HHcy诱导的损伤，采用CBS、CSE和3MST酶的单、双或三基因递送系统将用于增强Hcy向H2S的转化。除了证实初步研究结果外，还将进行进一步的研究，以更深入地了解 H2S 介导的 HHcy 促纤维化和促炎症作用引起的肾血管功能障碍的改善。这项研究是新颖的，因为它评估了基因递送作为改善 HHcy 诱导的微血管重塑、肾功能障碍和高血压的治疗选择。