Kidney Week

Abstract: TH-PO085

Divergent Sphingosine 1-Phosphate (S1P) Signaling Pathways Control Pericyte Function in AKI to CKD Transition

Session Information

• AKI: Inflammation, New Technologies, Omics
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Rudnicka, Kinga Patrycja, University of Virginia, Charlottesville, Virginia, United States

Kinga Patrycja Rudnicka,

• Tanaka, Shinji, University of Virginia, Charlottesville, Virginia, United States

Shinji Tanaka,

• Zheng, Shuqiu, University of Virginia, Charlottesville, Virginia, United States

Shuqiu Zheng,

• Bajwa, Amandeep, University of Virginia, Charlottesville, Virginia, United States

Amandeep Bajwa,

• Yao, Junlan, University of Virginia, Charlottesville, Virginia, United States

Junlan Yao,

• Rosin, Diane L., University of Virginia, Charlottesville, Virginia, United States

Diane L. Rosin,

• Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States

Mark D. Okusa,

Background

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD). S1P, a sphingolipid that regulates AKI and fibrosis, is produced by two different kinases, sphingosine kinase (SphK) 1 and 2, and after its export can bind to S1P1-S1P5 receptors. S1P1, a key player during AKI and CKD, is expressed in both endothelial cells (EC) and pericytes (PC; Foxd1Cre⁺) and plays an important role in angiogenesis and EC-PC communication. We showed previously that EC S1P1 is protective after ischemia reperfusion injury (IRI) and that the global Sphk2 KO has less fibrosis after AKI, however the role of S1P signaling in pericytes is unknown.

Methods

Folic acid (FA; 250 mg/kg) or vehicle (0.3 M NaHCO₃, Veh) was given ip to 12-14 wk old male Foxd1Cre⁺Sphk2^fl/fl (Sphk2KO), Foxd1Cre^– Sphk2^fl/fl (WT control), Foxd1Cre⁺S1P1^fl/fl (S1P1KO), and Foxd1Cre^–S1P1^fl/fl (WT) mice. For IRI kidneys were clamped for 26 min ischemia followed by 24h reperfusion (8-10 wk old mice). AKI (24-72h) was assessed by plasma creatinine (PCr), blood urea nitrogen (BUN), qPCR (Kim-1 and Ngal) and histology (H&E staining). 14 days after injection of FA or Veh to Sphk2 mice, PCr and BUN were measured, and kidneys were analyzed for fibrosis by picrosirius red staining and by qPCR for expression of fibrotic markers.

Results

After bilateral IRI, in S1P1KO mice PCr was lower than in WT (0.91 vs. 0.55). After FA, in S1P1KO mice PCr was lower (0.78 vs. 0.23 mg/dl, p<0.05), as was ATN score (78.6 vs. 53.6%, p<0.05), Kim1 (0.63 vs. 0.33 p<0.01) and Ngal (0.85 vs. 0.50, p<0.05). There was no difference between Sphk2KO and its WT control in PCr, BUN, Kim-1, Ngal or histology (days 1-3). However, by day 14, FA-treated Sphk2KO mice had less fibrosis (by histology), smaller increases in BUN (39.6 vs. 55.5 mg/dL, p<0.05), and smaller increases in expression of fibrosis-related genes (Col1a1, Col3a1, Acta2, fibronectin, and vimentin) than WT control mice.

Conclusion

These divergent results suggest that: 1) sphingolipid signaling through SphK2 and S1P1 in perivascular cells is critical in controlling the phenotype in AKI and CKD and 2) controlling intracellular S1P through sphingosine kinases and extracellular S1P1 may serve as specific therapeutic targets in both AKI and AKI-CKD transition.

Funding

• NIDDK Support