Abstract: TH-PO709

VEPTP Inhibition as a Vasculoprotective Strategy to Treat Diabetic Kidney Disease

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Carota, Isabel Anna, Northwestern University, Chicago, Illinois, United States
  • Bartlett, Christina S., Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Onay, Tuncer, Northwestern University, Chicago, Illinois, United States
  • Scott, Rizaldy P., Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States
  • Kenig-Kozlovsky, Yael, Feinberg cardiovascular Research Inst, Northwestern University, Chicago, Illinois, United States
  • Oladipupo, Sunday S., Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Breyer, Matthew D., Lilly Research Laboratories, Indianapolis, Indiana, United States
  • Quaggin, Susan E., Northwestern University, Chicago, Illinois, United States
Background

With a growing number of patients suffering from diabetic kidney disease new treatments to halt progression of DKD are urgently needed. Silenced Tie2 signaling following dysregulated expression of its ligands Angpt1 and 2 found in diabetic patients has been linked to increased mesangial expansion and glomerular scarring. Here we show that the endothelial specific phosphatase VEPTP is upregulated in kidney tissue of diabetic, hypertensive rodents, suggesting VEPTP as effector of reduced Tie2 activity in diabetes. Following this finding we investigated VEPTP inhibition as target to prevent deterioration of renal function and glomerular endothelium under diabetic conditions.

Methods

To test the impact of VEPTP blockade on the progression of DKD we postnatally deleted VEPTP in a model of diabetic hypertension (Akita/ReninAAV+) and followed the mice until 24 weeks of age, before evaluating renal function, blood pressure, ACR and renal histology as measurement for the degree of DKD.

Results

Genetic deletion of VEPTP in non-diabetic mice promotes Tie2 phosphorylation and eNOS signaling resulting in elevated glomerular filtration rates and decreased systolic blood pressure. At 24 weeks of age GFRs of Ak/Ren mice declined significantly compared to their start values, whereas GFRs from diabetic VEPTP iKOs maintained their baseline GFR values (Ak/Ren=242.6, Ak/Ren VEPTP iKO=480.3 ul/min). The prevention of decline in GFR over time correlated with lower elevation of urine albumin/creatinine ratios in diabetic VEPTP iKO compared to diabetic controls (Ak/Ren=1549.4, Ak/Ren/VEPTP iKO=741.2 ul/min). Additional histological analysis revealed that diabetic/hypertensive VEPTP deficient mice presented less glomerular scarring, mesangial expansion as well as a lower number of aSMA positive glomeruli. Analysis of kidney lysates from Ak/Ren/VEPTP iKO mice showed rescue of Tie2 phosphorylation levels compared to Ak/Ren mice, demonstrating that blockade of VEPTP slows the progression of renal complications under diabetic and hypertensive conditions by stabilizing Tie2 signaling.

Conclusion

Genetic loss of VEPTP causes increased TIE2 activity in diabetic hypertension, slowing the development of DKD in mice. In sum, we identify VEPTP as a candidate therapeutic target to protect the kidney from diabetic injury.

Funding

  • Commercial Support