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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094907-03
Application #
8629733
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rasooly, Rebekah S
Project Start
2012-04-27
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$237,000
Indirect Cost
$87,000
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Franceschini, Nora; Le, Thu H (2014) Genetics of hypertension: discoveries from the bench to human populations. Am J Physiol Renal Physiol 306:F1-F11
Chang, Jamison; Ma, Jennie Z; Zeng, Qing et al. (2013) Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK). Am J Physiol Renal Physiol 304:F348-55