Contribution of Gstm1 to the severity of hypertension and chronic kidney disease

Gstm1 对高血压和慢性肾脏病严重程度的影响

• 批准号: 8271475
• 负责人: Thu H. Le
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-27 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271475
• 关键词: 4 hydroxynonenal; Affect; African American; Aldehydes; Alleles; Antioxidants; Blood Pressure; Candidate Disease Gene; Cessation of life; Chromosome Mapping; Chronic Kidney Failure; Clinical; Complex; Consensus; Coronary Arteriosclerosis; Development; Dialysis procedure; Disease; Disease Progression; Disease susceptibility; End stage renal failure; Environment; Environmental Pollutants; Environmental Risk Factor; Enzymes; Etiology; Event; GSTM1 gene; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Glomerular Filtration Rate; Glutathione S-Transferase; Goals; Human; Hypertension; Individual; Inflammation; Injury; Kidney Diseases; Lipid Peroxidation; Lipids; Modeling; Molecular; Mus; Organ; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Predisposition; Prevention; Process; Proteins; Reactive Oxygen Species; Relative (related person); Renal Mass; Renal function; Risk; Role; Severities; Severity of illness; Stress; Testing; Therapeutic; Time; Variant; Xenobiotics; cohort; genetic variant; hazard; human disease; hypertension treatment; improved; insight; kidney vascular structure; member; migration; mouse model; novel; protein function; response; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Hypertension (HTN) is a leading cause of end-stage renal disease (ESRD) in the U.S. There is general consensus that oxidative stress is a common factor in the development of HTN and progression of chronic kidney disease (CKD). Hence, genetic variants that affect the capacity to handle oxidative stress may influence the severity of HTN and the outcome of kidney disease. We have identified the null variant of the GSTM1 gene, a member of the Nrf2 antioxidant pathway, as a modifier of hypertensive kidney disease progression. The gene product of GSTM1 is glutathione S-transferase m-1, or GSTM1 enzyme, that belongs to a superfamily of glutathione-S-transferases that metabolize xenobiotics and a broad range of reactive oxygen species (ROS), and the highly reactive aldehydes (RAs) that are end products of lipid peroxidation. Approximately 30-50% of humans are completely deficient of GSTM1 enzyme due to homozygous inheritance of the common GSTM1 null allele, GSTM1(0). Those with the GSTM1(0/0) genotype have increased risks of HTN. Using a mouse model, we previously found that Gstm1 is a strong candidate gene for susceptibility to renal vascular injury, and that reduced expression of Gstm1 causes increased vascular smooth muscle cell (VSMC) proliferation, migration and oxidative stress. In preliminary studies, we assessed the effect of GSTM1(0) in the African American Study of Kidney Disease (AASK) Trial cohort. We found that the hazard ratios (HR) for the time to glomerular filtration rate (GFR) event, dialysis or death in those with two or one null alleles relative to those with two active alleles were 2.15 (p=0.005) and 1.73 (p=0.03), respectively. Our study is the first to demonstrate an association between a genetic variant and the clinical outcomes of the AASK Trial participants with hypertensive kidney disease. Despite the strong evidence implicating a role of the null variant of GSTM1 in human diseases, direct proof of causality and the exact molecular mechanism by which loss of the gene product causes disease susceptibility have not been established. We suggest that genetic variants that cause even a modest decremental change in the expression of GSTM1 gene provide a permissive environment of exaggerated oxidative stress. We hypothesize that GSTM1 acts to modify the severity of HTN and kidney disease progression through its central role in metabolizing RAs. To test this hypothesis, we have generated a Gstm1-/- mouse line to determine the contribution of loss of Gstm1 to hypertension and CKD course. Aim 1 will define the impact of Gstm1 deletion on the susceptibility to and severity of hypertension, using three mouse models of HTN. Aim 2 will determine the role of the Gstm1-Nrf2 pathway in kidney disease severity and progression, using the ischemic reduction of renal mass model. Aim 3 will define the functional molecular effects of GSTM1 on NRF2 expression and on RAs and their protein targets. The relative contribution of the enzymatic and functional non-enzymatic domains of GSTM1 on VSMC proliferation, migration and oxidative stress will also be determined. PUBLIC HEALTH RELEVANCE: It is generally acknowledged that the pathogenesis of hypertension and chronic kidney disease involve a complex interaction between genetic and environmental factors. In a large African American cohort with hypertensive kidney disease, we have identified that those patients lacking the GSTM1 gene have worse clinical outcomes with respect to loss of kidney function, need for dialysis, or death. The GSTM1 gene product, GSTM1 enzyme, metabolizes a broad range of compounds, including drugs and the highly reactive aldehydes that are both environmental pollutants and endogenously generated end products of the oxidative degradation of lipids. Our application proposes to establish that the direct interaction between a genetic factor (loss of GSTM1) and environmental factors (reactive aldehydes) contribute to the severity and progression of hypertension and chronic kidney disease. Our studies may provide novel insights and potential new opportunities for improving the treatments of HTN and CKD in those patients that are most genetically susceptible.

描述（由申请人提供）：高血压 (HTN) 是美国终末期肾病 (ESRD) 的主要原因。人们普遍认为氧化应激是 HTN 发生和慢性肾病进展的常见因素（慢性肾病）。因此，影响处理氧化应激能力的基因变异可能会影响高血压的严重程度和肾脏疾病的结果。我们已经鉴定出 GSTM1 基因的无效变体（Nrf2 抗氧化途径的成员）作为高血压肾病进展的调节因子。 GSTM1 的基因产物是谷胱甘肽 S-转移酶 m-1，或称 GSTM1 酶，属于谷胱甘肽-S-转移酶超家族，可代谢异生物质和多种活性氧 (ROS) 以及高活性醛类。 RAs）是脂质过氧化的最终产物。由于常见 GSTM1 无效等位基因 GSTM1(0) 的纯合遗传，大约 30-50% 的人类完全缺乏 GSTM1 酶。具有 GSTM1(0/0) 基因型的人患高血压的风险增加。我们之前使用小鼠模型发现Gstm1是肾血管损伤易感性的强候选基因， Gstm1 表达减少会导致血管平滑肌细胞 (VSMC) 增殖、迁移和氧化应激增加。在初步研究中，我们评估了 GSTM1(0) 在非裔美国人肾脏疾病研究 (AASK) 试验队列中的效果。我们发现，肾小球滤过率 (GFR) 事件、透析或死亡的时间风险比 (HR) 具有两个或一个无效等位基因的患者相对于具有两个活性等位基因的患者分别为 2.15 (p=0.005) 和 1.73 (p=0.03)。我们的研究首次证明遗传变异与患有高血压肾病的 AASK 试验参与者的临床结果之间存在关联。尽管有强有力的证据表明 GSTM1 无效变体在人类疾病中的作用，但因果关系的直接证据以及基因产物缺失导致疾病易感性的确切分子机制尚未确定。我们认为，即使是导致 GSTM1 基因表达适度减少的遗传变异，也为过度氧化应激提供了宽松的环境。我们假设 GSTM1 通过其在 RA 代谢中的核心作用来改变 HTN 的严重程度和肾脏疾病的进展。为了检验这一假设，我们构建了 Gstm1-/- 小鼠系，以确定 Gstm1 缺失对高血压和 CKD 病程的影响。目标 1 将使用三种高血压小鼠模型来确定 Gstm1 缺失对高血压易感性和严重程度的影响。目标 2 将利用肾质量缺血减少模型确定 Gstm1-Nrf2 通路在肾脏疾病严重程度和进展中的作用。目标 3 将定义 GSTM1 对 NRF2 表达以及 RA 及其蛋白质靶标的功能性分子影响。 GSTM1 的酶促结构域和功能性非酶促结构域对 VSMC 增殖、迁移和氧化应激的相对贡献也将被确定。 公众健康相关性：人们普遍认为高血压和慢性肾病的发病机制涉及遗传因素和环境因素之间复杂的相互作用。在一个患有高血压肾病的大型非洲裔美国人队列中，我们发现那些缺乏 GSTM1 基因的患者在肾功能丧失、需要透析或死亡方面的临床结果更差。 GSTM1 基因产物 GSTM1 酶可代谢多种化合物，包括药物和高反应性醛类，这些化合物既是环境污染物，也是脂质氧化降解的内源性最终产物。我们的申请旨在确定遗传因素（GSTM1 缺失）和环境因素（反应性醛）之间的直接相互作用导致高血压和慢性肾病的严重程度和进展。我们的研究可能会提供新颖的见解和潜在的新机会，以改善遗传最易受影响的患者的高血压和慢性肾病的治疗。