Normal and Dysregulated Sphingolipid Metabolism: Contributions to Podocyte Injury and Beyond

Abstract

Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.

Keywords: ceramide; cerebroside; ganglioside; glomerular disease; lipid rafts; podocyte; podocytopathies; sphingolipid; sphingosine-1-phosphate.

Figure 1

Overview of typical sphingolipid structures. Sphingosine is an 18-carbon amino alcohol with a double bond between carbons 4 and 5 and comprises the backbone of all sphingolipids. Ceramides are a class of sphingolipids in which a sphingosine is attached to a fatty acid (R) of varying lengths through an amide linkage. Sphingomyelins consist of a ceramide molecule bound to a phosphocholine group at the primary carbon. Cerebrosides are a class of glycosphingolipids in which a ceramide is bound at the primary carbon to either glucose or galactose. The cerebroside shown here is glucocerebroside. Gangliosides consist of a ceramide bound to one or more sugar moieties that contain at least one sialic acid linked to the sugar chain. The ganglioside shown is GM3, which consists of a ceramide linked to a glucose which is attached to a galactose. The galactose has the sialic acid, N-acetylneuraminic acid or NANA, linked to it.

Figure 2

Overview of sphingolipid metabolism. ABCC1, ATP-binding cassette transporter C1; aCDase, acid ceramidase; akCDase, alkaline ceramidase; APOM, apolipoprotein M; aSMase, acid sphingomyelinase; CER, ceramide; CERK, ceramide kinase; CERS, ceramide synthase; CGT, Ceramide galactosyltransferase; CPTP, C1P transport protein; C1P, ceramide-1-phosphate; DES, dihydroceramide desaturase; DHC, dihydroceramide; DHS, Dihydrosphingosine; GluCer, glucosylceramide; GCST, galactosylceramide sulfotransferase; GSides, glycosides; GST, glycosyltransferase; HD, hexadecenal; 3-KDS, 3-ketodihydrosphinganine; KDSR, 3-ketodihydrosphingosine reductase; LacCer, lactosylceramide; LacCerS, LacCer synthase; LP, lipid phosphatase; MA-nSMase, mitochondria-associated neutral sphingomyelinase; nCDase, neutral ceramidase; nSMase, neutral sphingomyelinase; PE, phosphoethanolamine; SDase, sialidase; SGPL1, sphingosine-1-phosphate lyase 1; SM, sphingomyelin; SMS, sphingomyelin synthase; SPHK, sphingosine kinase; Spns2, sphingolipid transporter 2; SPP, sphingosine-1-phosphate phosphatase; SPT, serine-palmitoyl-transferase; ST, siayltransferases; ST3GalV, siayltransferases 5; S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor; and UGCG, UDP-glucose ceramide glucosyltransferase.