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Abstract: SA-OR18

VEGF-R2 Signaling in Renal Interstitium Exacerbates Post-AKI CKD Progression

Session Information

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

A dire consequence of acute kidney injury (AKI) is progression to chronic kidney disease (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. Peritubular capillary beds are significantly damaged during many types of AKI, which is closely associated with post-AKI CKD progression. Vascular endothelial growth factor (VEGF) is a well-defined angiogenic factor via its major receptor, VEGF receptor 2 (VegfR2). 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 VegfR2 signaling in renal interstitium remains poorly understood.

Methods

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 (iVegfR2RSC-/-) to interrogate timing specific role of VegfR2 in renal interstitial cells in AKI-to-CKD. 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. Renal blood flow was evaluated with arterial spin labeling MRI (ASL-MRI).

Results

We found that VegfR2RSC-/- mice have (I) reduced vascular injury and better blood flow post AKI, (II) are protected against AKI, and (III) have reduced AKI-to-CKD progression after renal IRI. Consistently, VegfR2RSC-/- are protected against progression to CKD in a cisplatin AKI-to-CKD model. Mechanistically, it appears that the VegfR2RSC-/- mice downregulate a maladaptive proliferation factor for pericytes, Thrombospondin-1 (TSP1). AKI triggers enhanced differentiation of a subpopulation of CD31+/ Foxd1+ cells, presumably caused by partial endothelial-mesenchymal transition (Endo-MT). Furthermore, iVegfR2RSC-/- mice are significantly protected against renal IRI.

Conclusion

These data suggest that VegfR2 signaling in renal interstitial cells exacerbates renal IRI and its post-AKI CKD progression as well as cisplatin AKI.

Funding

  • NIDDK Support