Abstract
Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite. S1P is produced from phosphorylation of sphingosine catalyzed by sphingosine kinases (SphK). SphK1/S1P signaling pathway is implicated in the progression of chronic kidney disease. We recently showed that knockout (KO) of SphK1 attenuated renal interstitial fibrosis in unilateral ureteral obstruction model. However, the role of SphK1/S1P pathway in the renal injury in hypertension has not yet been reported. The aim of this study was to test the hypothesis that SphK1/S1P signaling pathway mediates the kidney damage in DOCA‐salt hypertensive mice. Male wild type C57BL6 mice and Sphk1 KO mice were unilaterally nephrectomized and received a subcutaneous silicone strip containing 50 mg of deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water. At the 7th week, blood pressure was measured, 24h urine collected, and kidney tissues harvested. Four groups were studied: wild type control (WT‐C), wild type DOCA (WT‐DOCA), knockout control (KO‐C) and knockout DOCA (KO‐DOCA). There was no difference in DOCA‐salt‐induced hypertension between WT and KO mice (mean arterial pressure: 135.4 ± 6.1 mmHg vs. 130.4 ± 4.7 mmHg in WT‐DOCA and KO‐DOCA mice). The urine albumin was increased in two DOCA‐salt groups and that the KO‐DOCA group showed significantly lower urine albumin than WT‐DOCA mice (0.43 ± 0.09 mg/kg/24h in WT‐C, 19.36 ± 4.84 in WT‐DOCA, 0.52 ± 0.21 in KO‐C and 3.16 ± 0.74 in KO‐DOCA, P<0.05 for WT‐DOCA vs. KO‐DOCA). The glomerulosclerosis indices were significantly lower in KO‐DOCA than WT‐DOCA in kidney tissue slides with PAS staining (0.62 ± 0.12 in WT‐C, 1.93± 0.13 in WT‐DOCA, 0.43 ± 0.05 in KO‐C, and 1.31 ± 0.11 in KO‐DOCA, p<0.05 for WT‐DOCA vs. KO‐DOCA). The protein levels of α‐smooth muscle actin (α‐SMA) in kidney tissues were upregulated in both DOCA‐salt groups but were significant lower in KO‐DOCA group than in WT‐DOCA group. The relative protein levels of α‐SMA were 1.0 ± 0.1 in WT‐C, 3.97 ± 0.55 in WT‐DOCA, 1.12 ± 0.15 in KO‐C, and 1.61 ± 0.24 in KO‐DOCA (P<0.05 for WT‐DOCA vs. KO‐DOCA). These results suggest that Sphk1/S1P signaling pathway mediates kidney damage in DOCA‐salt hypertensive mice independent of blood pressure. Manipulating Sphk1/S1P signaling pathway may be used as a therapeutic strategy in kidney damage associated with hypertension. (Supported by NIH grant DK107991 to NL and DK54927 to PL)Support or Funding InformationNIH grant DK107991 to NL and DK54927 to PLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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