Abstract: FR-OR040

GSTM1 Deficiency Exaggerates Hypertension, Oxidative Stress, and Kidney Injury in Experimental Mouse Models of Hypertension and CKD

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Le, Thu H., University of Virginia, Charlottesville, Virginia, United States
  • Bodonyi-Kovacs, Gabor, Renal Division, George Washington University, Washington, District of Columbia, United States
  • Ruiz, Phillip, University Of Miami, Miami, Florida, United States
  • Cechova, Sylvia, University of Virginia, Charlottesville, Virginia, United States
Background

GSTM1 encodes the glutathione S-transferase m-1 (GSTM1) enzyme that belongs to a superfamily of phase II antioxidant enzymes. In humans, a common deletion mutation, the null allele GSTM1(0), results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. We reported that GSTM1(0) is associated with accelerated kidney disease progression in the African Americans Study of Kidney Disease (AASK). This has been confirmed in the Atherosclerosis Risk in Communities (ARIC) Study, in which GSTM1(0) is associated with incident kidney failure in both European Americans and African Americans.

Methods

To directly determine the impact of loss of GSTM1 enzyme on kidney disease development, we deleted Gstm1 in the mouse to determine its consequence in the angiotensin II model of hypertension (Ang II-HTN) and the surgical remnant model of chronic kidney disease (Nx-CKD).

Results

Compared to wild-type mice, Gstm1-/- mice display higher levels of urinary 8-isoprostane and a modest but significantly higher BP at baseline. In both Ang II-HTN and Nx-CKD models, Gstm1-/- mice have exaggerated HTN, increased superoxide levels and worse kidney injury, independent of activation of Nox2 and Nox4 NADPH oxidases. In AngII-HTN, Gstm1-/- mice display increased renal expression of genes involved in inflammation - CXCL-1, MCP-1, IL-1b and IL-6 – and increased renal macrophage infiltration. In the Nx-CKD model, deletion of Gstm1 resulted in early mortality, and significantly higher plasma creatinine and increased albuminuria. Isolated primary podocytes from Gstm1 KO mice also displayed a higher rate of migration in wound-healing assay.

Conclusion

In hypertension and CKD, GSTM1 enzyme may be protective by modulating oxidative stress and inflammation. Therapy directed at GSTM1 pathway in those genetically most susceptible may ameliorate kidney disease progression.

Funding

  • NIDDK Support