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.

Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with 13 C-encoded natural S1P as internal standard

“…The observed elevation of S1P in kidney of Fabry disease mice is of particular interest given the nephropathy with characteristic podocyte loss developing in Fabry disease patients. It has been recently proposed that sphingolipids play an important role in modulating podocyte function in glomerular disorders [43]. Moreover, it has been demonstrated that reduced sphingosine-1-phosphate lyase, the enzyme responsible for cellular S1P breakdown, induces podocyte-related glomerular proteinuria [44].…”

“…The Clinica Chimica Acta 459 (2016) [36][37][38][39][40][41][42][43][44] Abbreviations: 13 C 5 -S1P, 13 C 5 C18-S1P; C18-S1P-ene, C18-S1P-diene; Gb3, globotriaosylceramide;…”

Fabry Nephropathy

“…13,14 Ultrastructural morphology and cellular distribution of lysosomal storage material are the most useful criteria to differentiate Fabry disease from its mimics (Table). Indeed, no other renal lipidosis shows prominent and widespread myelin bodies in podocytes, mesangial cells, endothelial cells, proximal tubules, interstitial cells, and arterial endothelial cells.…”

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

“…Despite research efforts, the pathophysiology of CKD is still not fully understood, although vascular, glomerular and tubular events are implicated in the disease 91,92 . Furthermore, podocytes or visceral epithelial cells within the Bowman's capsule have a role in preventing protein escape into the urine and therefore the loss of podocytes has been associated with the development of diabetic neuropathy 93,94 . Aberrant mTOR activation is associated with this process and its inhibition by drugs such as rapamycin may be of a potential clinical benefit 93,95 .…”