title: Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).
abstract: 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.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jamison
authors.initials: J
authors.lastname: Chang
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Ma
authors.forename: Qing
authors.initials: Q
authors.lastname: Zeng
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cechova
authors.forename: Adam
authors.initials: A
authors.lastname: Gantz
authors.forename: Caroline
authors.initials: C
authors.lastname: Nievergelt
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Connor
authors.forename: Michael
authors.initials: M
authors.lastname: Lipkowitz
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D044383:Black People / Q000235:genetics / Q000706:statistics & numerical data; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000235:genetics / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D006977:Hypertension, Renal / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics* / Q000401:mortality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D009393:Nephritis / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics* / Q000401:mortality; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016032:Randomized Controlled Trials as Topic; D051436:Renal Insufficiency, Chronic / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D001741:Black or African American
chemical_list: D000447:Aldehydes; D005982:Glutathione Transferase; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C027576:4-hydroxy-2-nonenal