ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-OR55

Autocrine Signaling of Sphingosine 1 Phosphate in Kidney Perivascular Cells Promotes Inflammation and Fibrosis

Session Information

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
  • Zheng, Shuqiu, 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
  • 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 that is produced inside the cell by the action of sphingosine kinase (SphK) 1 and 2. S1P is exported from cells by spinster homolog 2 (Spns2) or major facilitator superfamily 2b (Mfsd2b), and then acts on five G protein-coupled S1P receptors, S1P1 to S1P5, to affect various cellular 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 local S1P signaling in kidney perivascular cells affects the progression of kidney fibrosis.

Methods

Male Foxd1Cre+ Sphk2fl/fl, Foxd1Cre+ S1pr1fl/fl, Foxd1Cre+ Spns2fl/fl, and their littermate control mice were used. For unilateral ischemia-reperfusion injury (IRI), left kidney was clamped; right nephrectomy was performed at day 13. In the folic acid model, folic acid (250 mg/kg) was intraperitoneally injected. Mice were euthanized at day 14 to evaluate kidney fibrosis. Primary kidney perivascular cells were isolated from kidneys and used for in vitro studies.

Results

Both in the unilateral IRI and folic acid models, Foxd1Cre+ Sphk2fl/fl and Foxd1Cre+ S1pr1fl/fl mice demonstrated better kidney function (plasma creatinine/blood urea nitrogen), less kidney fibrosis (histology) with less macrophage infiltration, and suppressed expression of fibrosis-related genes (Acta2, Col1a1, Col3a1) in the kidneys compared with control. In in vitro studies, perivascular cells with Sphk2 deficiency or S1pr1 knockdown expressed less proinflammatory cytokines/chemokines, such as Ccl2, Il6, Cxcl1, after treatment with TLR2/4 agonists compared with control cells. We further identified Spns2 as the S1P transporter expressed in kidney perivascular cells. Foxd1Cre+ Spns2fl/fl mice also showed protection against kidney fibrosis in the unilateral IRI model and Spns2-knockdown cells showed suppressed inflammatory signaling upon stimulation.

Conclusion

SphK2/S1P/Spns2/S1P1 axis enhances inflammatory signaling in perivascular cells on injury, which aggravates immune cell infiltration and subsequent fibrosis in the kidney.

Funding

  • NIDDK Support