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.