Kidney Week

Abstract: SA-OR14

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

Session Information

• Diabetic Kidney Disease: From Mechanisms to Treatment
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

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

Michael Wetzel, PhD



Michael Wetzel, Ph.D is currently a postdoctoral fellow in Dr. Alaa Awad’s lab at UT Health-San Antonio. Dr. Wetzel obtained his BS from Texas A&M University, MS from UT Health-San Antonio, and PhD in cell biology from University of Texas Medical Branch. He came to Dr. Awad’s lab in 2018, which focuses on diabetic kidney disease. Dr. Wetzel’s current work involves the role of arginine and nitric oxide interaction in diabetic kidney disease. This presentation for 2020 ASN is titled “Enhancing Kidney DDAH-1 Expression by Adenovirus Delivery Reduces ADMA and Ameliorates Diabetic Nephropathy”.

• Gao, Ting, Pennsylvania State University College of Medicine Department of Medicine, Hershey, Pennsylvania, United States

Ting Gao,

• Stanley, Kristen, University of Texas Health Science Center at San Antonio Department of Medicine, San Antonio, Texas, United States

Kristen Stanley,

• Cooper, Timothy K., National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Frederick, Maryland, United States

Timothy K. Cooper,

• Morris, Sidney M., University of Pittsburgh Department of Microbiology and Molecular Genetics, Pittsburgh, Pennsylvania, United States

Sidney M. Morris,

• Awad, Alaa S., University of Texas Health Science Center at San Antonio Department of Medicine, San Antonio, Texas, United States

Alaa S. Awad,

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