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KIDNEY FIBROSIS

Targeting perivascular S1P attenuates inflammation

Nature Reviews Nephrology volume 18, page 679 (2022)Cite this article

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Sphingosine 1-phosphate (S1P) contributes to inflammation, and drugs targeting its receptors are protective against kidney fibrosis in animal models, although adverse effects have limited their clinical application. Targeting S1P signalling in perivascular cells might represent an alternative therapeutic approach to regulate this pathway in the kidney, according to a study by Mark Okusa and colleagues.

Although transdifferentiation of perivascular cells into myofibroblasts has been implicated in kidney fibrosis, loss of Sphk2 in perivascular cells did not affect their α-smooth muscle actin levels. However, Sphk2 deletion reduced the activation of nuclear factor-κB, expression of inflammatory genes and secretion of monocyte chemoattractants in perivascular cells exposed to lipopolysaccharide (LPS). The response to other immune stimuli such as Toll-like receptor 2 (TLR2) agonists was similarly blunted in Sphk2–/– perivascular cells compared with controls. S1P supplementation abrogated these effects in Sphk2–/– cells exposed to LPS unless S1pr1 was also knocked down (but not the other genes encoding S1P receptors in perivascular cells). Deletion of S1pr1 in perivascular cells had a similar protective effect to that of Sphk2 deletion in the IRI model. In primary human kidney perivascular cells, treatment with an SPHK2 inhibitor lowered S1P levels and the secretion of pro-inflammatory cytokines in response to TLR2 and TLR4 agonists.

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References

Original article

  • Tanaka, S. et al. Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney. Sci. Transl. Med. 14, eabj2681 (2022)

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  1. Nature Reviews Nephrology http://www.nature.com/nrneph

    Monica Wang

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  1. Monica Wang
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Correspondence to Monica Wang.

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Wang, M. Targeting perivascular S1P attenuates inflammation. Nat Rev Nephrol 18, 679 (2022). https://doi.org/10.1038/s41581-022-00637-1

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