i(3)so3-galactosylceramide and Kidney-Diseases

Serum sulfatides are the major glycosphingolipids in lipoproteins. Although serum sulfatides are mainly synthesized and secreted by the liver, they are significantly decreased when the kidneys are impaired. Our recent experimental study using a murine protein-overload nephropathy model suggested a hypothetical mechanism whereby serum sulfatides were reduced due to kidney dysfunction. This was the result of decreased hepatic expression of a sulfatide synthetic enzyme, cerebroside sulfotransferase (CST), which is associated with systemic enhancement of oxidative stress. However, there is a possibility that the experimental process, protein-overload itself, directly affected the sulfatide metabolism and oxidative stress in the liver. To determine whether kidney dysfunction actually reduces the hepatic synthesis of sulfatides via oxidative stress, we examined sulfatide levels, the hepatic content of metabolic sulfatide enzymes, and the degree of oxidative stress in protein-overload mice subjected to renoprotective therapy using clofibrate, a representative hypolipidemic medicine. Protein-overload mice exhibited marked kidney injuries, enhancement of hepatic oxidative stress, decreased levels of serum and hepatic sulfatides, and decreased expression of hepatic CST. The clofibrate treatment attenuated kidney damage and hepatic oxidative stress while maintaining serum/hepatic sulfatide levels and hepatic CST content in the mice. Because clofibrate monotherapy without protein-overload treatment only minimally affected these hepatic parameters, the hepatic synthesis of sulfatides appeared to be strongly influenced by kidney dysfunction and subsequent oxidative stress. This study suggests that the crosstalk between kidney dysfunction and hepatic sulfatide metabolism is mediated by oxidative stress. These results should help to understand the phenomenon in patients with end-stage kidney disease.

Topics: Acute Disease; Animals; Clofibrate; Disease Models, Animal; Drug Antagonism; Female; Gene Expression Regulation, Enzymologic; Hypolipidemic Agents; Kidney; Kidney Diseases; Liver; Mice; Mice, 129 Strain; Oxidative Stress; Serum Albumin, Bovine; Sulfoglycosphingolipids; Sulfotransferases

We recently proposed serum sulfatides as a novel biomarker for cardiovascular disease in patients with end-stage renal failure (ESRF), based on the possible antithrombotic properties of this molecule. In this earlier study, the level of serum sulfatides was gradually decreased in parallel with kidney dysfunction; however the precise mechanism underlying this decrease was unknown. The aim of the present study was to investigate the mechanism underlying the decrease in serum sulfatide levels caused by kidney dysfunction in an experimental animal model. To produce a kidney dysfunction animal model, we prepared a mouse model of protein overload nephropathy. Using high-throughput analysis combined with matrix-assisted laser desorption ionisation time-of-flight mass spectrometry, we measured the levels of sulfatides in the sera, livers, small intestines and kidneys of protein overload nephropathy mice. As the disease progressed, the levels of sulfatides in sera decreased. Also, the levels in livers and small intestines decreased in a similar manner to those in sera, to approximately 60% of the original levels. On the contrary, those in kidneys increased by approximately 1.4-fold. Our results indicate that kidney dysfunction affects the levels of sulfatides in lipoprotein-producing organs, such as livers and small intestines, and lowers the levels of sulfatides in sera.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Intestine, Small; Kidney Diseases; Liver; Male; Mice; Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfoglycosphingolipids

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 4days, 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.

Topics: Acute Disease; Animals; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Kidney Diseases; Liver; Male; Mice; Mice, Mutant Strains; Oxidative Stress; PPAR alpha; Proteins; Sulfoglycosphingolipids; Sulfotransferases