scholarly journals Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK)

2013 ◽  
Vol 304 (4) ◽  
pp. F348-F355 ◽  
Author(s):  
Jamison Chang ◽  
Jennie Z. Ma ◽  
Qing Zeng ◽  
Sylvia Cechova ◽  
Adam Gantz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
African American ◽  
Kidney Disease ◽  
Disease Progression ◽  
Genetic Variants ◽  
Null Allele ◽  
African American Study ◽  
Null Alleles ◽  
American Study ◽  
Kidney Disease Progression

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis ( P = 0.04) and in the time to GFR event, dialysis, or death ( P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

Recruitment experience in the African American Study of Kidney disease and hypertension (AASK) pilot study

1996 ◽  
Vol 17 (4) ◽  
pp. S17-S33 ◽  
Author(s):  
Paul K. Whelton ◽  
Jeannette Y. Lee ◽  
John W. Kusek ◽  
Jeanne Charleston ◽  
Jennifer DeBruge ◽  
...  
Keyword(s):  
African American ◽  
Pilot Study ◽  
Kidney Disease ◽  
African American Study ◽  
American Study

Abstract 495: GSTM1 Deficiency Exacerbates Hypertension in the Remnant Model of Chronic Kidney Disease

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sylvia Cechova ◽  
Rosa Chan ◽  
Beverly Koller ◽  
Thu H Le
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Null Allele ◽  
Null Alleles ◽  
Hypertensive Nephrosclerosis ◽  
Baseline Systolic Blood Pressure ◽  
Glutathione S Transferases ◽  
Targeting Strategy ◽  
Multiple Chronic Diseases

There is a general consensus that oxidative stress is a factor in the progression of chronic kidney disease (CKD). Hence, genetic variants that affect the capacity to handle oxidative stress may influence the outcomes of CKD. One important class of enzymes that has evolved to combat the damaging effects of reactive oxygen species is the glutathione-S-transferases. In particular, the μ class isoform 1 (GSTM1) has emerged as a potential modifier of multiple chronic diseases in humans. Approximately 30%-50% of humans are completely deficient of the GSTM1 enzyme because of homozygous inheritance of the GSTM1 null allele, GSTM1(0). We have identified the GSTM1 gene as a modifier of disease progression in hypertensive nephrosclerosis (HN). In an ancillary study of the African American (AA) Study of Hypertension and Kidney Disease (AASK) Trial, we reported that participants carrying one ( 1/0 ) or two ( 0/0 ) null alleles had 1.7- and 2-fold higher risk of the composite outcome of a 50% decline in the glomerular filtration rate (GFR), dialysis, or death relative to those with two active alleles. Here, the objective of our study was to determine the consequence of deletion of Gstm1 on the course of chronic kidney disease induced by reduction of renal mass (RRM) model in mice. We generated Gstm1-/- (KO) mice on the 129S6 background through conventional gene targeting strategy. By radiotelemetry, Gstm1 KO mice displayed a modest but significantly higher baseline systolic blood pressure (SBP) compared to their wild type (WT, Gtsm1 +/+ ) littermates: KO (n = 5): 138.8 ± 1.3; WT (n = 5): 132.1 ± 1.1, p < 0.01. Baseline urinary isoprostane (ng/100 mg of body weight) was significantly higher in KO mice than WT mice (15.1 ± 2.9; WT: 8.0 ± 0.8, p < 0.04). Four weeks after sub-total nephrectomy, Gstm1 KO mice developed significantly more severe hypertension than WT mice. The average SBP over a 2 week recording by radiotelemetry was 154.0 ± 3.2 mm Hg in KO mice (n = 5), and 142.3 ± 4.2 in WT mice (n = 3), p < 0.01. The effects of deletion of Gstm1 on kidney function and histopathology are under investigation. In conclusion, loss of GSMT1 increases oxidative stress and exaggerates hypertension in the murine model of chronic kidney disease.

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