Abstract 121: Gstm1 Deletion Exaggerates Hypertension, Oxidative Stress, and Kidney Pathology in Angiotensin II Hypertension Independent of Nox2 and Nox4
Gstm1 gene encodes an enzyme that belongs to a superfamily of Glutathione-S-transferases that metabolize a broad range of reactive oxygen species. In the African American Study of Kidney Disease Trial (AASK), we reported that participants with decreased expression of GSTM1 as carriers of the GSTM1 null allele have accelerated kidney disease progression. To establish cause and effect, we generated Gstm1-/- (KO) mice and determined their response in angiotensin II (AngII)-induced hypertension (at 1000 ng/kg/min for 4 weeks). By radiotelemetry, Gstm1 KO mice (n=6) displayed a modest but significantly higher baseline systolic blood pressure (SBP, mmHg) compared to their wild type (WT) littermates (n=6): KO 135.8 ± 1.4; WT: 129.9 ± 1.2; P = 0.01. AngII augmented the difference in SBP between WT and KO mice (KO 175.4 ± 6.2; WT 158.0 ± 2.6, p = 0.04). There were no differences in albumin/creatinine ratio (μg/mg) either at baseline (KO 29.1± 4.1; WT 27.3 ± 2.9) or after 4 weeks of Ang II (KO 4657 ± 631.6; WT 4697.7 ± 533.8). By quantitative real-time PCR, the renal expressions of Nox2 and Nox4 genes were almost identical and not statistically different between WT and KO mice. However, by luminescence, Gstm1 KO mice had significantly increased levels of superoxide radicals: [counts/min/1 mg of dry tissue] KO 128 ± 12 vs. WT 42 ± 8.5; P < 0.0001. Furthermore, there was significantly worse kidney pathology in Gstm1 KO mice (Figure 1), including focal segmental glomerulosclerosis (FSGS), fibrosis, chronic inflammation and epithelial cell reactivity. In conclusion, loss of GSTM1 enzyme increases Ang II induced hypertension, oxidative stress and kidney injury independent of Nox2 or Nox4.
Author Disclosures: S. Cechova: None. F. Chan: None. P. Ruiz: None. T.H. Le: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; Thu H. Le: 1R01DK094907-03 Grant title: Contribution of Gstm1 to the severity of hypertension and chronic kidney disease.
- © 2015 by American Heart Association, Inc.