Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Abstract

Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.

Keywords: C1P; Ceramide; DKD; FSGS; Kidney; Podocyte; S1P; SMPDL3b; Sphingolipids.

Figure 1:

The biological roles of active sphingolipid metabolites. Ceramide, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) can be converted into each other and regulate many important functions in a cell. While the conversion of C1P to S1P and vice versa might be possible, it has not yet been confirmed experimentally.

Figure 2:

Suggested mechanism of the dysregulation of the sphingolipid machinery in glomerular diseases. The data summarized are related to the events in kidney cortex only. Decreased activity of desaturase (Degs2) results in the accumulation of dihydroceramides (DH-Cer) and causes accumulation of reactive oxygen species (ROS), which impairs ATP production and leads to apoptosis. Decreased activity of sphingosine-1-phosphate lyase 1 (Sgpl1) results in the accumulation of sphingosine-1-phosphate (S1P). At the plasma membrane, decreased activity of sphingomyelin phosphodiesterase 2 (Smpd2) affects ceramide (Cer) production, while elevated activity of alkaline ceramidase 2 Acer2) increases levels of sphingosine (Sph) and, as a consequence, S1P. Overproduction of S1P results in increased S1P efflux via S1P transporters (such as ATP-binding cassette transporters ABCA1, ABCG1, ABCC1 and S1P transporter Spns2), where S1P acts as a paracrine factor and activates S1P receptors (primarily, S1P receptor 1, S1Pr1), leading to overproduction of NAPDH oxidase (NOX), increased ROS production and apoptosis. Overexpression of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) blocks ceramide kinase (CERK) activity and the conversion of ceramide to ceramide-1-phosphate (C1P), which affects interaction between insulin receptor (IR) and caveolin-1 (Cav1), leading to decreased protein kinase B (AKT) phosphorylation and apoptosis. Accumulation of the ganglioside GM3 at the plasma membrane has a similar effect, causing displacement of IR from Cav1 and impaired AKT phosphorylation.