Abstract: PO0220
VEGF-R2 Signaling in Renal Stroma Exacerbates Post-AKI CKD Progression
Session Information
- AKI Mechanisms - 3
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chiba, Takuto, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
- Sims-Lucas, Sunder, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
Background
Acute Kidney Injury (AKI) is widespread, identified in 30% of post-operative and 50% of ICU patients, and associated with increased rates of chronic kidney disease (CKD) and end stage renal failure. Peritubular capillary beds are significantly damaged, and it causes vascular rarefaction during many types of AKI. Vascular rarefaction is closely associated with post-AKI CKD progression. Vascular endothelial growth factor (VEGF) is a well defined angiogenic protein via its major receptor, VEGF receptor 2 (VEGF-R2). However, prior work from others demonstrated a role of VEGF as a negative regulator of pericyte function and vessel maturation. The functional implications of the VEGF-R2 signaling in renal stroma remains poorly understood.
Methods
We generated genetic mouse models for renal stromal cells (RSCs)-specific loss-of-function of VEGF-R2 with constitutively expressed Foxd1-Cre (cVEGF-R2RSC-/-) and tamoxifen inducible Foxd1-Cre (iVEGF-R2RSC-/-). AKI/CKD models induced either by a renal ischemia/reperfusion injury (IRI) model or by low/dose repeated treatment of cisplatin were performed. Mice are monitored for the development of AKI and post-AKI CKD using serum chemistries and tissue analysis.
Results
cVEGF-R2RSC-/- protects against ischemic AKI in male and female mice. Specifically, cVEGF-R2RSC-/- reduces renal tubular injury and microvascular rarefaction. cVEGF-R2RSC-/- also mitigates CKD progression post ischemic-AKI. cVEGF-R2RSC-/- reduces expression of kidney injury markers, Havcr1 and Lcn2, in a cisplatin-AKI/CKD model. Interestingly, iVEGF-R2RSC-/- demonstrates higher degree of protection against ischemic AKI as compared to cVEGF-R2RSC-/- studies. We showed previously that cVEGF-R2RSC-/- shows mild defects in kidney development. Our new data suggests that iVEGF-R2RSC-/- bypasses deleterious effect by the mutation during kidney development.
Conclusion
These data suggest that VEGF-R2 signaling in renal stromal cells exacerbates ischemic AKI and its post-AKI CKD progression as well as cisplatin AKI.
Funding
- NIDDK Support