Abstract: SA-PO512
VEGFR2 Blockade Improves Renal Damage in the Experimental Model of Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Plaza, Anita, Universidad Austral de Chile, Valdivia, Chile
- Lavoz, Carolina, Universidad Austral de Chile, Valdivia, Chile
- Carpio, Daniel, Universidad Austral de Chile, Valdivia, Chile
- Ruiz-Ortega, Marta, Universidad Autonoma, Madrid, Spain
- Mezzano, Sergio A., Universidad Austral de Chile, Valdivia, Chile
Background
Chronic inflammation is the main feature of progressive kidney disease, including Diabetic Nephropathy (DN). Among the potential therapeutic targets of renal damage induced by diabetes, a pathogenic role for Gremlin has been described. Recent studies in our group have described that Gremlin activates the vascular endothelial growth factor-2 receptor (VEGFR2) associated with renal inflammation. The animal model BTBR ob/ob has been widely used for the study of DN, since it develops histological characteristics that resemble the human DN. In these mice, Gremlin expression increases at week 8 and remains elevated until week 20 of life. This model offers an opportunity to study the mechanisms that could lead to more specific therapies that lead to the regression of the DN.
Our aim was to evaluate the role of VEGFR2 blockade in the progression of the DN in the BTBR ob/ob model.
Methods
In this animal model, VEGFR2 was blocked with the pharmacological inhibitor SU5416. The inhibitor was administered to mice of 15 weeks of life, 3 times a week for 5 weeks and then sacrificed (0.1 mg per mouse, i.p). The parameters of weight and glycemia, the ratio of Albumin/Creatinine (ACR) in urine, glomerular and tubulointerstitial damage at the microscopic and ultrastructural level, as well as inflammatory and podocyte damage markers by real-time PCR and IHC were evaluated in non-diabetic, diabetic and diabetic SU5416-treated groups. (n:6-8 animals per group).
Results
VEGFR2 blockade improved the ACR during all period of study compared to diabetic group. At glomerular level, SU5416-treated mice showed lower cellularity and lower mesangial matrix expansion and decreased thickening of the glomerular basement membrane. Also, in the tubulointerstitial compartment, the inflammatory infiltrate decreased and some foci of tubular atrophy were observed.
In response to VEGFR2 blockade, there was a downregulation in the kidney damage markers (KIM1 and Ngal), in podocyte markers WT-1, Nphs-1 and Nphs2 and in the pro-inflammatory factors MCP-1, Rantes, IL-17A and IL-6. However, Gremlin levels were not affected. Decreased inflammatory infiltrating cells in SU5416-treated mice was histologically observed.
Conclusion
These data show that the Gremlin/VEGFR2 axis would be involved in kidney damage mediated by diabetes and could be a new therapeutic target for ND.
Funding
- Other NIH Support