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(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发展和慢性肾脏疾病(CKD)进展的共同因素。因此，影响氧化应激处理能力的基因变异可能会影响HTN的严重程度和肾脏疾病的结局。我们已经确定GSTM1基因的零变异是Nrf2抗氧化途径的成员，是高血压肾病进展的修饰物。谷胱甘肽转移酶1的基因产物是谷胱甘肽S转移酶m-1或谷胱甘肽转移酶1，属于谷胱甘肽-S转移酶超家族，代谢外源物质和多种活性氧物种(ROS)，以及作为脂质过氧化终产物的高活性醛(RAS)。大约30%-50%的人由于常见的GSTM1零等位基因GSTM1(0)的纯合遗传而完全缺乏GSTM1酶。GSTM1(0/0)基因携带者患HTN的风险增加。利用小鼠模型，我们先前发现GSTM1是肾血管损伤易感性的一个强有力的候选基因， 而GSTM1的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)试验队列中的作用。我们发现，发生肾小球滤过率(GFR)事件、透析或死亡的时间的危险比(HR) 携带2个或1个无效等位基因者分别为2.15(p=0.005)和1.73(p=0.0 3)。我们的研究首次证明了基因变异与高血压肾病AASK试验参与者的临床结果之间的关联。尽管有强有力的证据表明GSTM1零变异在人类疾病中的作用，但GSTM1零变异的直接因果关系和基因产物丢失导致疾病易感性的确切分子机制尚未建立。我们认为，即使引起GSTM1基因表达的轻微减量变化的遗传变异也提供了一个被夸大的氧化应激的容许环境。我们假设GSTM1通过其在RAS代谢中的中心作用来改变HTN的严重性和肾脏疾病的进展。为了验证这一假设，我们建立了一个GSTM1-/-小鼠品系，以确定GSTM1缺失对高血压和CKD病程的贡献。目的1利用三种HTN小鼠模型，确定GSTM1缺失对高血压易感性和高血压严重程度的影响。目的2利用肾脏缺血减少模型，确定GSTM1-Nrf2通路在肾脏疾病严重程度和进展中的作用。目的3将确定GSTM1对NRF2表达和RAS及其蛋白靶点的功能分子效应。GSTM1的酶和功能非酶结构域对VSMC增殖、迁移和氧化应激的相对贡献也将被确定。 公共卫生相关性：人们普遍认为，高血压和慢性肾脏疾病的发病机制涉及遗传和环境因素之间的复杂相互作用。在一大批患有高血压肾病的非裔美国人中，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酶代谢一系列化合物，包括药物和高活性醛，这些化合物既是环境污染物，也是脂类氧化降解的内源性最终产物。我们的申请表明，遗传因素(GSTM1缺失)和环境因素(活性醛)之间的直接相互作用有助于高血压和慢性肾脏疾病的严重程度和进展。我们的研究可能会为改进HTN和CKD的治疗提供新的见解和潜在的新机会，这些患者最容易受到遗传因素的影响。