Abstract: SA-PO126

Effective Therapy of Type 2 Diabetic Nephropathy by Protecting Pancreatic and Glomerular Endothelium with AAV10.COMP-Ang1

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
  • Tian, Mi, University of Utah Health, Salt Lake City, Utah, United States
  • Tang, Li, University of Utah Health, Salt Lake City, Utah, United States
  • Westenfelder, Christof, University of Utah Health, Salt Lake City, Utah, United States
Background

Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In the kidney, this results in the loss of podocytes and thereby constitutive angiopoietin (Ang)-1 signaling required for maintenance and stabilization of the glomerular endothelium. As a consequence, glomerular endothelial cells are damaged, leading to leakage, glomerulosclerosis, and renal failure, i.e., diabetic nephropathy (DN). Therefore, we hypothesized that replacing Ang1 by constitutively expressing it with the plasmid AAVrh10.COMP-Ang1 would improve glomerular architecture and function thereby reducing glomerulosclerosis in db/db mice, a model of T2DM.

Methods

Uninephrectomy was performed on all experimental mice at 8 wks of age. Three groups included non-diabetic db/m, untreated diabetic db/db control and diabetic db/db mice treated with a single dose of AAVrh10.COMP-Ang1 (2x1011 particles) injected via left carotid artery at 10 wks of age.

Results

The overexpression of COMP-Ang1 was confirmed not only in glomeruli but also in pancreatic and hepatic capillaries, which corrected the diabetes-induced dysregulation of tissue Ang2/Ang1 balance. Untreated db/db mice had substantial hyperglycemia (BG, 576±31mg/dl; Hb1Ac, 11.3±1.3%) and developed progressive increases in albuminuria and glomerular mesangial matrix expansion, associated with increased renal PAI-1, a1(IV) collagen and fibronectin expression compared with db/m mice at 18wks of age. Treatment with COMP-Ang1 yielded a significant reduction of glycemia (BG, 241±193mg/dl; Hb1Ac, 7.2±1.5%) and slowed the progression of albuminuria and glomerulosclerosis in db/db mice by 70% and 61%, respectively. Furthermore, renal expression of NF-kBp65, Nox2 and p47phox and pancreatic production of myeloperoxidase were increased while tissue SirT1 levels were decreased in untreated db/db mice, which were ameliorated by COMP-Ang1 overexpression.

Conclusion

These observations confirm our hypothesis and suggest that overexpression of COMP-Ang1 locally not only improves pancreatic function but also slows the progression of diabetes-associated glomerulosclerosis by improving both pancreatic and glomerular endothelial function via potently stimulating Ang1-Tie2 signaling. We conclude that upregulation of Ang1 expression locally has promise in improving glucose control and DN in T2DM.