Differential Branching of the Sphingolipid Metabolic Pathways with the Stage of Development

Abstract

We have studied sphingomyelin metabolism in the papillae of neonatal (10-day-old) and adult (70-day-old) kidneys of male Wistar rats because sphingolipid second messengers generated by sphingomyelin metabolism are involved in cellular processes such as proliferation, differentiation and apoptosis. We showed that sphingomyelin and ceramide concentrations in homogenized rat papilla tissue increase with the time whereas sphingosine-1-phosphate content decreases. This is consistent with the finding of a higher biosynthesis of the latter sphingolipid in neonatal than in adult rat papillae. De novo synthetized ceramide was, however, higher in adult than in neonatal papilla homogenates probably accounting for the high ceramide content of the adult rat papilla. These results suggest an active de novo pathway not ending in sphingomyelin but instead arresting at ceramide in adult rat papilla tissue, partially metabolized into sphingosine-1-phosphate in neonatal rat papillae. The activity and the expression of sphingosine kinase, one of the enzymes involved in ceramide metabolism, was found to be higher in neonatal than adult rat kidney tissue. The intracellular distribution of sphingosine kinase was also different; in neonatal rat tissue the enzyme was predominantly associated with plasma membranes but it was cytosolic in adult rat papilla tissue. These findings seem to indicate that, in rat renal papillae, the developmental regulation of sphingosine kinase expression and activity addresses the sphingolipid metabolism to the formation of the proliferative metabolite sphingosine-1-phosphate in the neonatal period, and ceramide, which is associated with cell arrest and differentiation in the adult tissue. These data are consistent with the proliferative state necessary for tubular elongation during the neonatal period and the maintenance of the differentiated state in the adult tissue.

Dynamic regulation of sphingosine-1-phosphate homeostasis during development of mouse metanephric kidney

“…Studies of sphingolipid content in kidneys of neonatal and adult rats found highest concentrations of S1P during the neonatal period that decreased with age, while ceramide and sphingomyelin content increased with age (11). Although these studies examined S1P content postnatally, the results are consistent with our findings of increased SPP activity and lower S1P content in mature kidneys.…”

Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

“…In vitro studies show that such stimuli include hypoxia/reoxygenation [ 31 , 32 , 50 , 51 , 52 ], oxidants [ 33 , 53 , 54 ], UV light [ 38 , 39 , 55 ], heat stress [ 56 ], oxalate [ 54 , 57 ], P-fimbriae of E. coli [ 58 , 59 ], nephrotoxins, including cadmium [ 60 , 61 ], isoflurane [ 62 ], microcystin [ 63 ], nickel [ 64 ], and radiocontrast [ 65 ], Shiga-toxin B [ 58 ], staphylococcal enterotoxin B [ 66 ], interleukin (IL)-1β [ 59 ] and TNF-α [ 54 , 59 ]. In vivo studies show that ceramide is accumulated in kidneys exposed to anti-glomerular membrane (GBM) antibody [ 52 ], nephrotoxins such as carbon tetrachloride [ 67 ] and isoflurane [ 62 ], developing kidney [ 68 , 69 ], ischemia/reperfusion (I/R) injury [ 51 , 52 ], glycerol-induced myohemoglobinuria [ 52 ], and obstructive nephropathy [ 70 ]. These stimuli can induce apoptosis, and an apoptogenic role of ceramide is further supported by the ability of exogenous ceramide to induce apoptosis in RTCs [ 50 , 63 , 68 , 71 ].…”

Changes in ceramide metabolism are essential in Madin-Darby canine kidney cell differentiation

“…We have previously reported that renal collecting duct cells regulate the branching of sphingolipid metabolism depending on the stage of cellular differentiation (25). Further, we demonstrated that, during hypertonicity-induced differentiation, MDCK cells develop a program of sphingolipid metabolism that includes a FB1-resistant increase in GSLs (14) and SM synthesis (15).…”