Acute kidney injury induced by protein-overload nephropathy down-regulates gene expression of hepatic cerebroside sulfotransferase in mice, resulting in reduction of liver and serum sulfatides |
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Authors: | Xiaowei Zhang Yuji Kamijo Gang Li Reiji Kannagi Toshifumi Aoyama |
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Affiliation: | a Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan b Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan c Cardiac Centre of Hebei Provincial People’s Hospital, 348 Hepingxi Road, Shijiazhuang 050051, People’s Republic of China d The Second Hospital of Hebei Medical University, 205 Heping Road, Shijiazhuang 050011, People’s Republic of China e Division of Molecular Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan f Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan |
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Abstract: | Sulfatides, possible antithrombotic factors belonging to sphingoglycolipids, are widely distributed in mammalian tissues and serum. We recently found that the level of serum sulfatides was significantly lower in hemodialysis patients than that in normal subjects, and that the serum level closely correlated to the incidence of cardiovascular disease. These findings suggest a relationship between the level of serum sulfatides and kidney function; however, the molecular mechanism underlying this relationship remains unclear. In the present study, the influence of kidney dysfunction on the metabolism of sulfatides was examined using an established murine model of acute kidney injury, protein-overload nephropathy in mice. Protein-overload treatment caused severe proximal tubular injuries within 4 days, and this treatment obviously decreased both serum and hepatic sulfatide levels. The sphingoid composition of serum sulfatides was very similar to that of hepatic ones at each time point, suggesting that the serum sulfatide level is dependent on the hepatic secretory ability of sulfatides. The treatment also decreased hepatic expression of cerebroside sulfotransferase (CST), a key enzyme in sulfatide metabolism, while it scarcely influenced the expression of the other sulfatide-metabolizing enzymes, including arylsulfatase A, ceramide galactosyltransferase, and galactosylceramidase. Pro-inflammatory responses were not detected in the liver of these mice; however, potential oxidative stress was increased. These results suggest that down-regulation of hepatic CST expression, probably affected by oxidative stress from kidney injury, causes reduction in liver and serum sulfatide levels. This novel mechanism, indicating the crosstalk between kidney injury and specific liver function, may prove useful for helping to understand the situation where human hemodialysis patients have low levels of serum sulfatides. |
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Keywords: | ARSA, arylsulfatase A CGT, ceramide galactosyltransferase COX2, cyclooxygenase-2 CST, cerebroside sulfotransferase GALC, galactosylceramidase GAPDH, glyceraldehyde-3-phosphate dehydrogenase HNE, 4-hydroxynonenal LS, lysosulfatides d18:2, sphingadienine d18:1, (4E)-sphingenine d18:0, sphinganine t18:0, phytosphingosine d20:1, (4E)-icosasphingenine d20:0, icosasphinganine t20:0, 4D-hydroxyicosasphinganine MALDI-TOF MS, matrix-assisted laser desorption ionization-time of flight mass spectrometry MDA, malondialdehyde NF-κB, nuclear factor-κB NOX, nonphagocytic oxidase PCR, polymerase chain reaction PPAR, peroxisome proliferator-activated receptor SD, standard deviation SEM, standard error of the mean Sp1, specificity protein 1 TNFα, tumor necrosis factor-α |
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