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

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.

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

“…Recent clinical studies have revealed a significant reduction in serum sulfatide levels in the final stage of chronic kidney disease, which is strongly correlated with a high incidence of cardiovascular disease at this stage [51][52][53]. Other studies using a kidney dysfunction mouse model have demonstrated that kidney injuries cause simultaneous reductions in the levels of sulfatides in serum and liver, which is associated with the down-regulation of hepatic CST expression [4,5]. Furthermore, our recent study demonstrated that hepatic PPARα activation and resulting hepatic CST induction caused an increase in serum sulfatide concentration [8].…”

“…However, it is unknown whether PPARα plays an important role in the transcriptional regulation of CST in other organs, such as kidney, heart, brain, and digestive tract. Specifically, we previously reported that opposing responses concerning CST induction and tissue sulfatide contents between liver and kidney were found in the kidney dysfunction murine model [4,5], 7 which suggests organ-specific regulation of sulfatide metabolism. Therefore, extended studies using multiple murine tissues are needed to determine the role of PPARα in murine CST gene regulation.…”

“…However, there is little information about the transcriptional regulators for these key enzymes in sulfatide metabolism. We previously 6 reported that CST gene expression was affected by oxidative stress and inflammation in mice [4,5]. We have proposed several transcription factors involved in these phenomena by searching through the upstream regions of the mouse CST gene [4][5][6][7].…”

Quantitative imaging mass spectrometry of renal sulfatides: validation by classical mass spectrometric methods

“…In all analyses, blood-derived lipids were not separately taken into account. However, serum sulfatide levels are less than 0.2% of kidney sulfatide levels and therefore negligible ( 36 ).…”

Role of sulfatide in normal and pathological cells and tissues

“…Various antigen-presenting cells, such as dendritic cells, macrophages, subsets of B kidney dysfunction lowers the level of sulfatide in serumw through downregulation of CST gene expression in lipoprotein-producing organs such as the liver ( 56,57 ). Reduction of serum sulfatide level in patients with end-stage renal disease was detected prior to induction of hemodialysis therapy ( 58 ).…”