RESUMEN
Sphingolipids (SLs) are bioactive signaling molecules essential for various cellular processes, including cell survival, proliferation, migration, and apoptosis. Key SLs such as ceramides, sphingosine, and their phosphorylated forms play critical roles in cellular integrity. Dysregulation of SL levels is implicated in numerous diseases, notably chronic kidney disease (CKD). This review focuses on the role of SLs in CKD, highlighting their potential as biomarkers for early detection and prognosis. SLs maintain renal function by modulating the glomerular filtration barrier, primarily through the activity of podocytes. An imbalance in SLs can lead to podocyte damage, contributing to CKD progression. SL metabolism involves complex enzyme-catalyzed pathways, with ceramide serving as a central molecule in de novo and salvage pathways. Ceramides induce apoptosis and are implicated in oxidative stress and inflammation, while sphingosine-1-phosphate (S1P) promotes cell survival and vascular health. Studies have shown that SL metabolism disorders are linked to CKD progression, diabetic kidney disease, and glomerular diseases. Targeting SL pathways could offer novel therapeutic approaches for CKD. This review synthesizes recent research on SL signaling regulation in kidney diseases, emphasizing the importance of maintaining SL balance for renal health and the potential therapeutic benefits of modulating SL pathways.
RESUMEN
Sphingosine 1-phosphate (S1P) and FTY720-phosphate (FTYp) increased intracellular calcium in cells expressing S1P1 mCherry-tagged receptors; the synthetic agonist was considerably less potent. Activation of protein kinase C by phorbol myristate acetate (PMA) blocked these effects. The three agents induced receptor phosphorylation and internalization, with the action of FTYp being more intense. S1P1 receptor-Rab protein (GFP-tagged) interaction was studied using FRET. The three agents were able to induce S1P1 receptor-Rab5 interaction, although with different time courses. S1P1 receptor-Rab9 interaction was mainly increased by the phorbol ester, whereas S1P1 receptor-Rab7 interaction was only increased by FTYp and after a 30-min incubation. These actions were not observed using dominant negative (GDP-bound) Rab protein mutants. The data suggested that the three agents induce interaction with early endosomes, but that the natural agonist induced rapid receptor recycling, whereas activation of protein kinase C favored interaction with late endosome and slow recycling and FTYp triggered receptor interaction with vesicles associated with proteasomal/lysosomal degradation. The ability of bisindolylmaleimide I and paroxetine to block some of these actions suggested the activation of protein kinase C was associated mainly with the action of PMA, whereas G protein-coupled receptor kinase (GRK) 2 (GRK2) was involved in the action of the three agents.