Sphingosine kinase and sphingosine-1-phosphate regulate epithelial cell architecture by the modulation of de novo sphingolipid synthesis

Abstract

Sphingolipids regulate several aspects of cell behavior and it has been demonstrated that cells adjust their sphingolipid metabolism in response to metabolic needs. Particularly, sphingosine-1-phosphate (S1P), a final product of sphingolipid metabolism, is a potent bioactive lipid involved in the regulation of various cellular processes, including cell proliferation, cell migration, actin cytoskeletal reorganization and cell adhesion. In previous work in rat renal papillae, we showed that sphingosine kinase (SK) expression and S1P levels are developmentally regulated and control de novo sphingolipid synthesis. The aim of the present study was to evaluate the participation of SK/S1P pathway in the triggering of cell differentiation by external hypertonicity. We found that hypertonicity evoked a sharp decrease in SK expression, thus activating the de novo sphingolipid synthesis pathway. Furthermore, the inhibition of SK activity evoked a relaxation of cell-cell adherens junction (AJ) with accumulation of the AJ complex (E-cadherin/β-catenin/α-catenin) in the Golgi complex, preventing the acquisition of the differentiated cell phenotype. This phenotype alteration was a consequence of a sphingolipid misbalance with an increase in ceramide levels. Moreover, we found that SNAI1 and SNAI2 were located in the cell nucleus with impairment of cell differentiation induced by SK inhibition, a fact that is considered a biochemical marker of epithelial to mesenchymal transition. So, we suggest that the expression and activity of SK1, but not SK2, act as a control system, allowing epithelial cells to synchronize the various branches of sphingolipid metabolism for an adequate cell differentiation program.

Bioavailable wine pomace attenuates oxalate-induced type II epithelial mesenchymal transition and preserve the differentiated phenotype of renal MDCK cells

“…In contrast, an absence of cell proliferation takes place in oxalate-treated MDCK cells pre-treated with rWPP and wWPP bioavailable fractions by preventing an increase in cell numbers and maintaining β-catenin in the AJ. A possible explanation for this observation is the modulatory effect of polyphenols on Wnt pathway activation, which is required for β-catenin transcriptional activity activation (Bazzoni and Dejana, 2004;Sferrazza et al, 2020). Under normal conditions, free β-catenin is phosphorylated and degraded however this phosphorylation can be inhibited by Wnt pathway activation (Bazzoni and Dejana, 2004).…”

“…In vertebrates, cell–cell junctions can be classified into four functional classes: adherens junctions and desmosomes, which mechanically link cells by bridging the cytoskeleton of adjacent cells, communicating junctions, or gap junctions, which chemically and electrically couple neighboring cells, and occluding junctions, or tight junctions, which are essential for establishing barrier functions across a cell layer ( Wei and Huang, 2013 ). In adherens Junction (AJ) complexes, the extracellular domain of the transmembrane protein E-cadherin interacts with cadherins within neighboring cells and the intracellular tail provides the scaffold for the armadillo family members (such as β-catenin, plakoglobin/β-catenin, and p120-catenin), which bind the cadherin tails and anchor cytoskeletal adapter proteins (such as β-catenin), which in turn anchor the AJ to the cytoskeleton and improve the stability of the AJ ( Santacreu et al., 2019 ). Beta-catenin and E-cadherin localize in the periphery of the cells delineating cell morphology, both under isoosmolarity and hyperosmolarity as we saw for the pre- and post-treated cells with the rWPP and wWPP.…”

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

“…Overexpression of S1P phosphatase degraded S1P, resulting in decreased S1P levels and maintained ceramide levels, which resulted in an increase in the ratio of ceramide/S1P, leading to apoptosis in HEK cells exposed to oxidative stress/ceramide [ 266 ]. Studies with gene engineering showed that knock-down of SphK1/S1P increased ceramide production by de novo ceramide synthesis or the salvaging pathway in RTCs [ 267 , 268 ], which resulted in an increased ratio of ceramide/S1P, leading to apoptosis and the inhibition of cell proliferation. In contrast, the overexpression of SphK1 increased S1P but decreased ceramide levels in HEK cells [ 269 ].…”

La esfingosina 1-fosfato (S1P) como mediador de los efectos biológicos de la hormona folículo-estimulante (FSH) en células de la granulosa de bovino

“…Mediante la vía de reciclaje, la ceramida puede ser hidrolizada por ceramidasas y producir esfingosina, finalmente, por acción de la (SK), la esfingosina será fosforilada formándose así S1P (Santacreu et al, 2019). La síntesis de S1P esta mediada por dos isoformas de SK, esfingosina cinasa 1 (SK1) y esfingosina cinasa 2 (SK2) las cuales difieren en secuencia, propiedades bioquímicas, localización subcelular y funciones (Gupta et al, 2019).…”