Rapid kidney changes resulting from glycosphingolipid depletion by treatment with a glucosyltransferase inhibitor

Abstract

The ceramide analog, -threo-1-phenyl-2-decanoylamino-3-morpholino-1-morpholino-1-propanol, inhibits the glucosylation of ceramide and thus, by virtue of the normal catabolism of the higher glucosphingolipids, leads to a general depletion of cellular glucolipids. In a previous study with chronic administration of this inhibitor in mice, it was found that the kidneys and liver, particularly the former, grew more poorly than the organs of control mice. This study shows that the inhibitor produces rapid decreases in glucolipid concentration in kidney which are maintained for at least 5 days without noticeable harm. The changes were enhanced by inclusion of -cycloserine in the injection scheme. Cycloserine blocks ketosphinganine synthase and thus slows the synthesis of all sphingolipids. However, sphingomyelin levels did not drop significantly in this study. The glucosyltransferase inhibitor also produced a small decrease in kidney [beta]--glucuronidase and distinct increases in the levels of glucocerebrosidase, galactocerebrosidase and sphingomyelinase. It also produced a small but distinct decrease in the level of glucosyltransferase, after a delay of a few hours, possibly because the inhibitor was metabolized to a covalently inactivating product. Comparison with kidney, liver and brain showed that the kidney was more sensitive to the action of the morpholino inhibitor.