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Abstract: SA-OR14

Enhancing Kidney DDAH-1 Expression by Adenovirus Delivery Reduces Asymmetric Dimethylarginine and Ameliorates Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wetzel, Michael, University of Texas Health Science Center at San Antonio Department of Medicine, San Antonio, Texas, United States
  • Gao, Ting, Pennsylvania State University College of Medicine Department of Medicine, Hershey, Pennsylvania, United States
  • Stanley, Kristen, University of Texas Health Science Center at San Antonio Department of Medicine, San Antonio, Texas, United States
  • Cooper, Timothy K., National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Frederick, Maryland, United States
  • Morris, Sidney M., University of Pittsburgh Department of Microbiology and Molecular Genetics, Pittsburgh, Pennsylvania, United States
  • Awad, Alaa S., University of Texas Health Science Center at San Antonio Department of Medicine, San Antonio, Texas, United States
Background

Endothelial dysfunction, characterized by reduced bioavailability of nitric oxide and increased oxidative stress, is a hallmark characteristic in diabetes and diabetic nephropathy (DN). High levels of asymmetric dimethylarginine (ADMA) are observed in several diseases including DN and are a strong prognostic marker for cardiovascular events in patients with diabetes and end-stage renal disease. ADMA, an endogenous endothelial nitric oxide synthase (NOS3) inhibitor, is selectively metabolized by dimethylarginine dimethylaminohydrolase (DDAH). Low DDAH levels have been associated with cardiac and renal dysfunction, but its effects on DN are unknown. We hypothesized that enhanced renal DDAH-1 expression would improve DN by reducing ADMA and restoring NOS3 levels.

Methods

DBA/2J mice injected with multiple low doses of vehicle or streptozotocin were subsequently injected intrarenally with adenovirus expressing DDAH-1 (Ad-h-DDAH-1) or vector control [Ad-green fluorescent protein (GFP)], and mice were followed for 6 wk.

Results

Diabetes was associated with increased kidney ADMA (p<0.05) and reduced kidney DDAH activity (p<0.05) and DDAH-1 expression (p<0.05) compared to normal mice but had no effect on kidney DDAH-2 expression. Ad-GFP-treated diabetic mice showed significant increases in albuminuria (p<0.005), histological changes (p<0.005), glomerular macrophage recruitment (p<0.001), inflammatory cytokine (p<0.01) and fibrotic markers (p<0.01), kidney ADMA levels (p<0.05), and urinary thiobarbituric acid reactive substances excretion (p<0.001) as an indicator of oxidative stress, along with a significant reduction in kidney DDAH activity (p<0.05) and kidney NOS3 mRNA (p<0.05) compared with normal mice. In contrast, Ad-h-DDAH-1 treatment of diabetic mice reversed these effects.

Conclusion

These data indicate, for the first time, that DDAH-1 mediates renal tissue protection in DN via the ADMA-NOS3-interaction. Enhanced renal DDAH-1 activity could be a novel therapeutic tool for treating patients with diabetes.

Funding

  • NIDDK Support