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Knockout of Sphingosine Kinase 1 Attenuates Renal Interstitial Fibrosis in Unilateral Ureteral Obstruction (UUO) Model
Author(s) -
Zhang Xiwen,
Wang Fan,
Wang Weili,
Li PinLan,
Comlekoglu Tien,
Li Ningjun
Publication year - 2017
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.31.1_supplement.1030.29
Subject(s) - sphingosine kinase 1 , chemistry , sphingosine , sphingosine kinase , medicine , endocrinology , kinase , sphingosine 1 phosphate , receptor , biochemistry
Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite and an important signaling molecule that plays a significant role in the differentiation of fibroblasts to myofibroblasts. S1P synthesis is catalyzed by sphingosine kinases (SPHK), which phosphorylate sphingosine into S1P. The present study tested the hypothesis that Sphk1‐S1P signaling pathway participates in the kidney damage in unilateral ureteral obstruction (UUO) model using Sphk1 knockout mice. UUO was created by ligation of the ureter on one kidney and the contralateral kidney is used as control. Wild type C57BL6 mice and Sphk1 KO mice were subjected to UUO for 14 days and four groups of kidneys were collected: wild type control group (WT‐C), wild type UUO group (WT‐UUO), knockout control group (KO‐C) and knockout UUO group (KO‐UUO). The mRNA level of Sphk1 in WT‐UUO was increased by 4 fold (p<0.05 vs. WT‐C) and there was no significant difference between other three groups. The protein levels of α‐smooth muscle actin (α‐SMA) and collagen I were upregulated in both UUO groups but the levels were significant lower in KO‐UUO group than in WT‐UUO group. The relative protein levels of α‐SMA were 1 ± 0.03 in WT‐C, 18.13 ± 2.55 WT‐UUO, 1.95 ± 0.67 KO‐C, and 9.54 ± 3.55 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO; collagen I levels were 1 ± 0.13 in WT‐C, 11.25 ± 1.74 WT‐UUO, 0.93 ± 0.58 KO‐C, and 3.09 ± 1.15 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO. Immunostaining showed that the percentage of lymphocyte marker CD43 positive cells was much higher in both UUO groups than in two control groups, but there was no significant difference between KO‐UUO and WT‐UUO, suggesting that the differences of renal fibrotic markers between WT‐UUO and KO‐UUO are not due to the change of immune regulation by knockout of Sphk1, rather, it is the direct effect of Sphk1 knockout on renal cells. Finally, the tubular injury score and glomerulosclerosis index were significantly lower in KO‐UUO than in WT‐UUO in kidney tissue slides with PAS staining (Tubular injury score: 0.07 ± 0.01 in WT‐C, 2.66 ± 0.17 WT‐UUO, 0.03 ± 0.02 KO‐C, and 1.21 ± 0.16 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO; Glomerulosclerosis index: 0.62 ± 0.12 in WT‐C, 2.24 ± 0.14 WT‐UUO, 0.43 ± 0.05 KO‐C, and 1.50 ± 0.10 KO‐UUO, p<0.05 for KO‐UUO vs. WT‐UUO). These results suggest that Sphk1‐S1P signaling pathway mediates kidney damage in UUO mice. Manipulating Sphk1‐S1P signaling pathway may be used as a therapeutic strategy in renal interstitial fibrosis. Support or Funding Information Support: NIH grant HL89563