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Pharmacological Tie2 activation in kidney transplantation
Kristina Thamm1, Florence Njau1, Paul Van Slyke1
1Kristina Thamm, Florence Njau, Joon-Keun Park, Hermann Haller, Sascha David, Department of Nephrology and Hypertension, Medical School Hannover, 30625 Hannover, Germany.
Aim:
To investigate the therapeutic potential of vasculotide (VT) - a Tie2 activating therapeutic - in kidney transplantation.
Methods:
We performed a murine MHC-mismatched renal transplant model (C57Bl/6 male into Balb/c female) with 60 min cold and 30 min warm ischemia time. 500 ng VT was administered i.p. to donor mice 1 h before organ removal. In addition, recipients received 500 ng VT i.p. directly and 3 d after surgery. Survival was monitored and remaining animals were sacrificed 28 d after transplantation. In this model, we analyzed: (1) organ function; (2) Kaplan-Meier survival; (3) organ damage (periodic acid Schiff staining) via semi-quantitative scoring [0-4 (0 = no injury/inflammation to 4 = very severe injury/inflammation)]; (4) expression of renal endothelial adhesion molecules (ICAM-1) via immunofluorescence (IF) staining, immunoblotting and qPCR; (5) infiltration of inflammatory cells (IF Gr-1, F4/80); and (6) fibrosis via staining of α-smooth muscle actin (αSMA), Sirius red staining and immunoblotting of SMAD3 activation.
Results:
Exogenous activation of Tie2 with VT resulted in diminished expression of peritubular and glomerular endothelial adhesion molecules. Consequently, infiltration of inflammatory cells (analyzed as ICAM-1, Gr-1 and F4/80 positive cells) was reduced in VT-treated mice compared to controls. Additionally, VT was protective against fibrogenesis after kidney transplantation. Trends towards lower serum creatinine (vehicle: 142 ± 17 μmol/L vs VT: 94 ± 23 μmol/L), urea (vehicle: 76 ± 5 mmol/L vs VT: 60 ± 8 mmol/L) and lactate dehydrogenase (vehicle: 1288 ± 383 iU vs VT: 870 ± 275 iU) were observed on day 6 after transplantation. Kaplan-Meier survival analysis showed improved survival rates in the VT-treated mice that did not reach statistical significance (27% vs 54%, P = 0.24, n = 11 per group). Exogenous activation of Tie2 via VT might reduce infiltration of inflammatory cells into renal tissue thereby protecting the transplant from early graft dysfunction potentially affecting long-term function.
Conclusion:
Protection of the endothelial microvasculature via the Tie2 axis in the early transplant setting might hold promise as a therapeutic target.
Insights
Vasculotide (VT), a Tie2 activator, reduced inflammatory cell infiltration and protected against fibrosis in a kidney transplant model. This suggests Tie2 activation may be a promising therapeutic target for early transplant protection.
Area of Science:
- Nephrology
- Transplantation Immunology
- Vascular Biology
Background:
- Kidney transplantation is a critical treatment for end-stage renal disease.
- Early graft dysfunction and long-term complications remain significant challenges.
- The Tie2 signaling pathway plays a crucial role in endothelial cell function and vascular integrity.
Purpose of the Study:
- To investigate the therapeutic potential of vasculotide (VT), a Tie2 activating agent, in a murine kidney transplant model.
- To assess the impact of VT on inflammatory cell infiltration, organ damage, and fibrosis post-transplantation.
Main Methods:
- A murine MHC-mismatched renal transplant model with defined ischemia times was utilized.
- Vasculotide (VT) was administered to donor mice and recipients.
- Organ function, survival rates, histological damage, endothelial adhesion molecules, inflammatory cell infiltration, and fibrosis were analyzed.
Main Results:
- VT treatment diminished endothelial adhesion molecules and reduced inflammatory cell infiltration (ICAM-1, Gr-1, F4/80 positive cells).
- VT showed protective effects against fibrogenesis and trends towards improved organ function (creatinine, urea, LDH).
- Survival rates were improved in VT-treated mice, though not statistically significant.
Conclusions:
- Protection of the endothelial microvasculature via the Tie2 axis is a promising therapeutic strategy in the early phase of kidney transplantation.
- VT may mitigate early graft dysfunction by reducing inflammatory cell infiltration.
- Targeting the Tie2 pathway holds potential for improving long-term transplant outcomes.
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