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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rasooly, Rebekah S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Liang, Jingjing; Le, Thu H; Edwards, Digna R Velez et al. (2017) Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. PLoS Genet 13:e1006728
Sung, Sun-Sang J; Li, Li; Huang, Liping et al. (2017) Proximal Tubule CD73 Is Critical in Renal Ischemia-Reperfusion Injury Protection. J Am Soc Nephrol 28:888-902
Sung, Sun-Sang J; Ge, Yan; Dai, Chao et al. (2017) Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. J Immunol 198:2589-2601
Chu, Pei-Lun; Gigliotti, Joseph C; Cechova, Sylvia et al. (2017) Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II. J Am Soc Nephrol 28:1826-1837
Niu, Feiyang; Zhou, Jianhui; Le, Thu H et al. (2017) Testing the trajectory difference in a semi-parametric longitudinal model. Stat Methods Med Res 26:1519-1531
Keller 4th, T C Stevenson; Butcher, Joshua T; Broseghini-Filho, Gilson BrĂ¡s et al. (2016) Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (Hb?X). Hypertension 68:1494-1503
Mahajan, Anubha; Rodan, Aylin R; Le, Thu H et al. (2016) Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. Am J Hum Genet 99:636-646
Bodonyi-Kovacs, Gabor; Ma, Jennie Z; Chang, Jamison et al. (2016) Combined Effects of GSTM1 Null Allele and APOL1 Renal Risk Alleles in CKD Progression in the African American Study of Kidney Disease and Hypertension Trial. J Am Soc Nephrol 27:3140-3152
Billaud, Marie; Chiu, Yu-Hsin; Lohman, Alexander W et al. (2015) A molecular signature in the pannexin1 intracellular loop confers channel activation by the ?1 adrenoreceptor in smooth muscle cells. Sci Signal 8:ra17
Franceschini, Nora; Le, Thu H (2014) Genetics of hypertension: discoveries from the bench to human populations. Am J Physiol Renal Physiol 306:F1-F11

Showing the most recent 10 out of 12 publications