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Inhibition of Sphingosine Kinase 2 Attenuated Cisplatin‐induced Nephrotoxicity in Mice
Author(s) -
Xie Dengpiao Li,
Hu Gaizun,
Wang Weili,
Li Pin-Lan,
Chen Chaoling,
Li Ningjun
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06411
Subject(s) - sphingosine , sphingosine kinase , nephrotoxicity , sphingolipid , cisplatin , endocrinology , chemistry , medicine , kidney , sphingosine 1 phosphate , kinase , pharmacology , biochemistry , chemotherapy , receptor
Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite and shown to participate in various kidney diseases. S1P is produced by sphingosine kinases (Sphks), which phosphorylate sphingosine into S1P. It has been demonstrated that knockout of Sphk2 gene protects the kidneys in unilateral ureteral obstruction model. The present study tested the hypothesis that inhibition of Sphk2 protects the kidneys against cisplatin‐induced nephrotoxicity. Male C57BL6 mice were divided into three groups: vehicle (Ctrl), cisplatin + vehicle (Cis) and cisplatin + ABC294640, a Sphk2 inhibitor (Cis + in). Cisplatin (10 mg/Kg) was given by weekly i.p. injection and Sphk2 inhibitor (35 mg/Kg) gavage every other day for 4 weeks. Plasma creatinine levels were significantly higher in Cis group than that in Ctrl, whereas it was significantly lower in Cis+in group than that in Cis (mean: 0.17 ± 0.02, 0.38 ± 0.05, and 0.20 ± 0.02 mg/dL in Ctrl, Cis and Cis+in group, respectively, p<0.05). Western blot analysis showed that the levels of fibrotic protein alpha‐smooth muscle actin (α‐SMA) in the kidneys were significantly increased in Cis group and that this increase in α‐SMA was blocked in Cis+in group. The relative α‐SMA protein levels were 1.0 ± 0.04, 1.8 ± 0.11 and 0.8 ± 0.19 in Ctrl, Cis and Cis+in group, respectively (p<0.05). The increased level of Kidney Injury Molecule‐1 was also significantly reduced in Cis+in group compared with that in Cis group. These results suggest that Sphk2 pathway mediates cisplatin‐induced kidney damage. Manipulating Sphk2 may be used as a therapeutic strategy in the management of cisplatin‐induced nephrotoxicity. Support or Funding Information NIH grants R01DK54927, R01DK107991, R01HL145163