Podocyte pathology and nephropathy - sphingolipids in glomerular diseases

Abstract

Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay-Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann-Pick, and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarly, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD), HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS), and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

Keywords: ASMase; S1P; SMPDL3b; ceramide; glomerular disease; kidney disease; podocyte; sphingolipid.

Figure 1

Structure of sphingolipids. In sphingolipids, the hydrophobic region consists of a longchain sphingoid base with generally 18 carbons, such as sphingosine, which is linked to the acyl group of a fatty acid via an amide bond (R2). The hydrophilic region (R1) consists in the simplest case of a hydroxyl group in the case of ceramide.

Figure 2

Sphingolipid metabolism. Ceramide is the centerpiece of the sphingolipid metabolic pathway and can be synthesized de novo from l-serine and palmitoyl-CoA (green), through hydrolysis of sphingomyelin (yellow), or through hydrolysis of glycosphingolipids and sulfatites (purple). Ceramide can also be synthesized from sphingomyelin through the action of sphingomyelinases, or from ceramide-1-phosphate through the action of ceramide-1-phosphate phosphatase. Finally, ceramide can be further catabolized (blue) to sphingosine and sphingosine-1-phosphate, which are biologically active metabolites and finally to ethanolamine-1-phosphate and C16 fatty aldehydes. SPT, serine palmitoyl transferase; 3-KSR, 3-ketosphinganine reductase; CS, ceramide synthetase; DES, dihydroceramide desaturase; SMase, sphingomyelinase; SMS, sphingomyelin synthetase; PC, phosphatidylcholine; DAG, diacylglycerol; C1PPase, ceramide-1-phosphate phosphatase; CK, ceramide kinase; CDase, ceramidase; CS, ceramide synthase; SK, spingosine kinase; S1PP, spingosine-1-phosphate phosphatase; GCS, glycosylceramide synthase; GCase, glycosylceramidase; GalCS, galactosylceramide synthase; Gal-CDase, galactosylceramidase.