VEGF-R2 Signaling in Renal Stroma Exacerbates Post-AKI CKD Progression
- AKI: Mechanisms - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Chiba, Takuto, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Oda, Akira, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Sims-Lucas, Sunder, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
A dire consequence of AKI is progression to CKD. AKI patients are at more than twice the increased risk of progressive CKD that leads to excessive morbidity and mortality. Understanding the mechanisms by which AKI progresses to CKD is essential for establishing a new therapeutic target since no established therapy to date is available for. Renal microvasculature, including pericytes and endothelial cells, are damaged in AKI, leading to recruitment of inflammatory cells which contributes to progression to CKD. It was recently shown that Platelet-derived growth factors (PDGFs) are predicted to signal via VEGF-R2, particularly in disease conditions. However, the functional implications of VEGF-R2 in the renal stroma, which gives rise to renal pericytes, in CKD remain poorly understood. This informed us an overarching hypothesis that renal stroma specific VEGF-R2 signaling dysregulates microvascular recovery and exacerbates post-AKI progression to CKD.
We generated genetic mouse models for renal stromal cells (RSCs)-specific loss-of-function of VegfR2 with constitutively expressed Foxd1-Cre (VegfR2RSC-/-) as well as tamoxifen inducible Foxd1-Cre (iVEGF-R2RSC-/-) to interrogate timing specific role of VegfR2 in renal stroma in AKI-to-CKD. CKD models induced either by a renal ischemia/reperfusion injury (IRI) or by low/dose repeated treatment of cisplatin were performed. Mice were monitored for the development of AKI and post-AKI CKD using serum chemistries and tissue analysis.
We found that VegfR2RSC-/- mice have reduced inflammation and vascular injury after renal IRI and have reduced renal intertitial fibrosis after renal IRI as well as reduced interstitial lipid deposition. Consistently, VegfR2RSC-/- are protected against progression to CKD in a cisplatin CKD model. Mechanistically, VegfR2RSC-/- kidneys have reduced expression of a pro-inflammatory signaling axis of Thrombospondin-1 (TSP1)/ CD148 and have increased expression of fatty acid metabolism associated genes contributing to the enhanced protection. Furthermore, iVegfR2RSC-/- mice are significantly protected against renal IRI.
These data suggest that VEGF-R2 signaling in renal stroma exacerbates renal IRI and its CKD progression as well as cisplatin CKD.
- NIDDK Support