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Kidney Week

Abstract: PO0597

Sphingosine Kinase 2 in Kidney Perivascular Cells Promotes Inflammation and Fibrosis Through S1PR1 Signaling

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Tanaka, Shinji, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Kharel, Yugesh, Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Zheng, Shuqiu, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Lipsey, Jonathan E., Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
  • Rosin, Diane L., Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Lynch, Kevin, Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States
  • Okusa, Mark D., Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, United States
Background

Sphingosine 1-phosphate (S1P) is a sphingolipid, which is produced by two different kinases, sphingosine kinase (SphK) 1 and 2. S1P is exported through Spns2 or Mfsd2b, and then reacts with S1P receptors (S1PR1-5) to affect myriad cell functions. We recently showed that Sphk2/ mice were protected from renal fibrosis when compared to wild type or Sphk1/ mice (PMID: 27799486). We hypothesized that Sphk2 deletion in renal perivascular cells confers the protection from progressive kidney fibrosis.

Methods

Male Foxd1Cre+ Sphk2fl/fl and Foxd1CreSphk2fl/fl (control) mice were used. For unilateral ischemia-reperfusion injury (IRI), left kidney was clamped for 30 min; right nephrectomy was performed at day 13. For bilateral IRI, both kidneys were clamped for 30 min. Mice were euthanized at day 14 to evaluate kidney fibrosis (unilateral IRI) and at day 1 to evaluate the extent of acute kidney injury (bilateral IRI). Primary kidney perivascular cells were isolated from kidneys of Foxd1Cre+ Sphk2fl/fl and control mice.

Results

In the unilateral IRI model, Foxd1Cre+ Sphk2fl/fl mice demonstrated better kidney function (plasma creatinine), less kidney fibrosis (histology) with less macrophage infiltration, and suppressed expression of fibrosis-related genes (Acta2, Col1a1, Col3a1) in the kidneys compared with control mice but there was no difference in plasma S1P between the groups. In contrast, in the bilateral IRI model, there was no difference between the groups in kidney function, kidney Havcr1/Lcn2 expression, and histology at day 1. In in vitro studies, Sphk2-deficient perivascular cells expressed less inflammatory cytokines, such as Ccl2, Il6, Cxcl1, after LPS stimulation compared with control perivascular cells. Sphk2-deficient and control perivascular cells robustly expressed Spns2, but not Mfsd2b, and S1pr1-3 among the five S1P receptor subtypes. Among S1pr1-3, only knockdown of S1pr1 resulted in suppressed expression of inflammatory cytokines after LPS stimulation.

Conclusion

Sphk2 deletion in renal perivascular cells was protective against kidney fibrosis. In vitro studies suggested that S1P produced by Sphk2 is exported through Spns2 and reacts with S1PR1 to enhance the inflammatory signal in these cells, leading to immune cell infiltration and subsequent fibrosis in the kidneys.

Funding

  • NIDDK Support