Abstract: TH-OR016

Endothelial Marker Expressing Stromal Cells Are Important Regulators of Recovery from AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Maringer, Katherine V., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Mukherjee, Elina, None, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Acute Kidney Injury (AKI) is characterized by an abrupt decrease in renal function that can lead to renal failure, contributing to morbidity and mortality. We have identified a subset of endothelial marker expressing stromal (EMES) cells that contribute to peritubular capillary endothelium. The peritubular capillaries are the primary sites of damage during AKI. We have previously shown that EMES cells are important during the injury phase of AKI. Subsequently, we hypothesize that EMES cells are important contributors to recovery after AKI.

Methods

To determine the importance of EMES following ischemia reperfusion injury (IRI) we utilized lineage tracing, using a TdTomato reporter (labeling all EMES cells) and interrogated the percentage of EMES cells present in IRI and contralateral kidneys. We then interrogated re-expression of stromal genes using RT-PCR. Furthermore, we generated mice with a conditional deletion of Flk1 (Vegfr2, essential for vascular development) in Foxd1cre positive renal stroma (Flk1ST-/-), and evaluated tissue after blood flow dependent AKI, utilizing (IRI), and blood flow independent/nephrotoxic AKI utilizing cisplatin and focused on the recovery phase (7, or 28 days) post injury.

Results

We determined that EMES cells were upregulated 7 days after IRI contributing to vascular recovery. We next determined following both AKI models that developmental stromal genes were re-expressed, suggestive of stromal de-differentiation, which may drive EMES proliferation. To interrogate the importance of EMES cells after AKI, we used Flk1ST-/- animals subjected to IRI or cisplatin, and found mutants had less perfusion and increased HIF1a expression at 7 days in IRI models while cisplatin treatment had no change in perfusion but increased HIF1a. In both models, persistent proximal tubule de-differentiation was observed in mutants. Furthermore, 28 days after injury mutants contained significant fibrosis, and damage compared to controls.

Conclusion

Following AKI the renal stroma requires de-differentiation and re-expression of developmental stromal genes prior to proliferation and re-differentiation. This coupled with EMES cell proliferation, reestablishes normal oxygen concentrations and regulates HIF signaling to modulate repair and recovery from AKI.

Funding

  • NIDDK Support