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: 8820806
• 负责人: Thu H. Le
• 金额: $ 23.7万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820806
• 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; Patient risk; Patients; Pharmaceutical Preparations; Phase; 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; phase III trial; 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.

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，普遍认为氧化应激是HTN发展和慢性肾病（CKD）进展的共同因素。因此，影响处理氧化应激能力的遗传变异可能影响HTN的严重程度和肾脏疾病的结局。我们已经确定了GSTM1基因的零变体，Nrf2抗氧化途径的成员，作为高血压肾病进展的修饰因子。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 -转移酶超家族，代谢异种生物和多种活性氧（ROS），以及作为脂质过氧化最终产物的高活性醛（RAs）。由于常见的GSTM1零等位基因GSTM1(0)的纯合遗传，大约30-50%的人完全缺乏GSTM1酶。GSTM1（0/0）基因型的人患HTN的风险增加。通过小鼠模型，我们之前发现Gstm1是肾血管损伤易感性的强候选基因，