Sphingolipids and Redox Signaling in Renal Regulation and Chronic Kidney Diseases

Abstract

Significance: Sphingolipids play critical roles in the membrane biology and intracellular signaling events that influence cellular behavior and function. Our review focuses on the cellular mechanisms and functional relevance of the cross talk between sphingolipids and redox signaling, which may be critically implicated in the pathogenesis of different renal diseases. Recent Advances: Reactive oxygen species (ROS) and sphingolipids can regulate cellular redox homeostasis through the regulation of NADPH oxidase, mitochondrial integrity, nitric oxide synthase (NOS), and antioxidant enzymes. Over the last two decades, there have been significant advancements in the field of sphingolipid research, and it was in 2010 for the first time that sphingolipid receptor modulator was exploited as a therapeutic in humans. The cross talk of sphingolipids with redox signaling pathways becomes an important mechanism in the development of many different diseases such as renal diseases. Critical Issues: The critical issues to be addressed in this review are how sphingolipids interact with the redox signaling pathway to regulate renal function and even result in chronic kidney diseases. Ceramide, sphingosine, and sphingosine-1-phosphate (S1P) as main signaling sphingolipids are discussed in more detail. Future Directions: Although sphingolipids and ROS may mediate or modulate cellular responses to physiological and pathological stimuli, more translational studies and mechanistic pursuit in a tissue- or cell-specific way are needed to enhance our understanding of this important topic and to develop effective therapeutic strategies to treat diseases associated with redox signaling and sphingolipid cross talk. Antioxid. Redox Signal. 28, 1008-1026.

Keywords: NADPH oxidase; free radicals; inflammation; sphingolipids.

FIG. 1.

Production and metabolism of signaling sphingolipids. CER can be produced by an initial reaction via de novo synthesis pathway, which involves the decarboxylation of a serine residue and condensation with a fatty acyl-CoA that is catalyzed by SPT. It can also be produced by hydrolysis of SM through different SMases. Subsequent enzymatic reactions are catalyzed by 3-keto dihydrosphingosine reductase, CerS, and dihydro-CER desaturases (sphingolipid δ (4)-desaturase DES1 and sphingolipid δ(4)-desaturase/C4 monooxygenase DES2), which determine the production of CER or related precursors for the majority of many other active sphingolipids such as SPH and S1P. C1PP, ceramide-1-phosphate phosphatase; CDase, ceramidases; CER, ceramide; CK, ceramide kinase; CerS, ceramide synthase; DAG, diacylglycerol; GCase, glucocylceramidase; GCS, glucosylceramide synthase; PC, phosphatidylcholine; S1P, sphingosine-1-phosphate; S1PP, S1P-phosphatase; SK, sphingosine kinase; SMase, sphingomyelinase; SMS, sphingomyelinase synthase; SPL, S1P lyase; SPT, serine palmitoyl transferase.

FIG. 2.

Intracellular machinery of sphingolipids and the SM cycle. De novo biosynthesis of sphingolipids begins at the cytosolic leaflet of the ER where a set of four enzymes coordinately generate CERs of different acyl chain lengths from nonsphingolipid precursors. In brief, sphinganine (dihydrosphingosine) is acylated to dihydro-CER and further desaturated to form CER, which starts with the condensation of serine and palmitoyl CoA via serine palmitoyltransferase. Once CER is transported to the Golgi complex, various head groups can be added to produce more complicated forms of sphingolipids such as SM or glycosphingolipids. SM is also transported to lysosomes where ASM converts it into CER and then to Sph by AC enzyme. AC, acid ceramidase; ASM, acid sphingomyelinase; AGC, acid glycosylceramidase; C1P, ceramide-1-phosphate; CERT, ceramide transport protein; CERK, ceramide kinase; CPTP, C1P-specific transfer protein; GSLs, glycosphingolipids; GluCer, glucosylceramide; NSM, neutral sphingomyelinase; SM, sphingomyelin; SphK, sphingosine kinases; Sph, sphingosine. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Ceramide-mediated formation and action of MRRSPs. In response to various stimuli such as death receptor activation, lysosomes are mobilized to move and fuse to the cell membrane, where aSMase from lysosomes is activated to produce ceramide leading to MR clustering. During MR clustering, Nox subunits or related cofactors are aggregated and thereby assembled to form MRRSPs producing O₂^.−, conducting transmembrane signals. MRRSP-mediated ROS production has been shown to contribute to NLRP3 inflammasome activation, which serves as intracellular machinery to turn on the inflammatory response in many different cells. GDP, guanosine diphosphate; GTP, guanosine triphosphate; MR, membrane raft; MRRSP, membrane raft redox signaling platform; NADPH, nicotinamide adenine dinucleotide phosphate; NLRP3, NLR family pyrin domain containing 3; Nox, NADPH oxidase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

ROS or free radical fragmentation of signaling sphingolipids. Chemical structure of some sphingolipids may be changed when they interact with ROS or other free radicals. Free radical-induced fragmentation may occur in 1. sphingosine, 2. CER, and 3. SM under different conditions such as radiation or HOCl stimulation as well as formation of a 2-hexadecenal (Hex). ROS, reactive oxygen species.

FIG. 5.

Interactions between S1P and ROS. Cross talk between S1P and redox signaling. In response to various stimuli such as different danger factors, ROS can be generated from different resources and may activate SPHK1 to generate S1P to produce intracellular signaling action regulating the cellular activity or organ function. S1P may also be transported out of cells through its transporter such as the Spns2, where it binds to its receptor to exert regulatory role such as S1P1. The binding of S1P to S1P1 receptor may activate Nox4 to produce O₂^.− that leads to redox signaling or regulation. S1PR, S1P receptors; Spns2, sphingolipid transporter 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Role of interactions between ceramide and ROS within podocytes in activation of inflammasomes to produce glomerular injury. Various pathogenic stimuli (including CER-associated raft clustering) produce ROS resulting in activation of NLRP3 inflammasome. In addition, lysosomal CER produced via aSMase in response to different stimuli may regulate cathepsin B release, which may induce NLRP3 inflammasome activation to trigger inflammatory response and tissue injury, including podocyte damage and other cell dysfunctions, together leading to glomerular fibrosis. Cathp B, cathepsin B; DAMP, danger-associated molecular pattern; IL-β, interleukin-β; IL-18, interleukin-18. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Role of interactions of sphingolipids with ROS in the development of renal interstitial lesion and fibrosis. In response to different pathological stimuli such as hypoxia, hypercholesterolemia, mechanical stress, or others, CER or S1P may be increasingly produced, which may lead to renal tubular cell injury or death such as apoptosis activating inflammation and myofibroblast formation, which produce tubulointerstitial ECM deposition and fibrosis. ECM, extracellular matrix. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

General model of sphingolipid–ROS interactions in chronic kidney disease. The production of major sphingolipids such as CER, SPH or S1P may be altered by different pathogenic factors, which can be activated or inhibited directly or indirectly through redox signaling or regulation. These sphingolipids also interact with ROS or other free radicals to lead to cell injury or death, activation of inflammasomes and inflammation, and initiation of fibrogenesis, ultimately resulting in CKD via their downstream signaling mechanisms or through interactions with each other. CKD, chronic kidney disease. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars