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）：在美国，高血压（HTN）是终末期肾脏疾病（ESRD）的主要原因，普遍的共识是，氧化应激是HTN发展和慢性肾脏疾病（CKD）发展的共同因素。因此，影响处理氧化应激能力的遗传变异可能会影响HTN的严重程度和肾脏疾病的结果。我们已经将NRF2抗氧化剂途径的成员GSTM1基因的空变体确定为高血压肾脏疾病进展的修饰符。 GSTM1的基因产物是谷胱甘肽S-转移酶M-1，或GSTM1酶，属于谷胱甘肽-S-转移酶的超家族，它们代谢异种生物和多种活性氧（ROS）（ROS），以及高度活性的αHyhydes（Ras）（Ras）（ras），是Endexient forexient for lipic的。由于公共GSTM1无效等位基因GSTM1（0），大约30％至50％的人完全缺乏GSTM1酶。患有GSTM1（0/0）基因型的人的HTN风险增加。使用小鼠模型，我们以前发现GSTM1是肾血管损伤易感性的强大候选基因， 降低GSTM1的表达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）在非裔美国人的肾脏疾病研究（AASK）试验队列中的影响。我们发现，肾小球过滤率（GFR）事件，透析或死亡的危险比（HR）在 相对于具有两个活性等位基因的两个或一个无效等位基因的人分别为2.15（p = 0.005）和1.73（p = 0.03）。我们的研究是第一个证明遗传变异与高血压肾脏疾病参与者的临床结果之间存在关联的研究。尽管有强有力的证据暗示了GSTM1无效变体在人类疾病中的作用，但直接证明因果关系和确切的分子机制，其基因产物丧失导致疾病易感性尚未建立。我们建议，GSTM1基因表达的遗传变异甚至会导致适度的降低变化，这为夸张的氧化应激提供了允许的环境。我们假设GSTM1通过其在代谢RAS中的核心作用来改变HTN和肾脏疾病进展的严重程度。为了检验这一假设，我们已经生成了GSTM1 - / - 小鼠线，以确定GSTM1损失对高血压和CKD课程的贡献。 AIM 1使用三种HTN小鼠模型，定义GSTM1缺失对高血压敏感性和严重程度的影响。 AIM 2将使用肾脏质量模型的缺血性降低，确定GSTM1-NRF2途径在肾脏疾病严重程度和进展中的作用。 AIM 3将定义GSTM1对NRF2表达以及RAS及其蛋白靶标的功能分子效应。还将确定GSTM1的酶促和功能性非酶结构域对VSMC增殖，迁移和氧化应激的相对贡献。 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理涉及遗传和环境因素之间的复杂相互作用。在大型非裔美国人与高血压肾脏疾病的队列中，我们已经确定缺乏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较差。 GSTM1基因产物GSTM1酶代谢了广泛的化合物，包括药物和高反应性醛是环境污染物和脂质氧化降解的最终产物。我们的应用建议确定遗传因素（GSTM1的丧失）与环境因素（反应性醛）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。我们的研究可能会提供新的见解和潜在的新机会，以改善那些在遗传上最易感的患者中HTN和CKD的治疗方法。