Sphingomyelinase‐like phosphodiesterase 3b mediates radiation‐induced damage of renal podocytes

Abstract

The molecular mechanisms responsible for the development of proteinuria and glomerulosclerosis in radiation nephropathy remain largely unknown. Podocytes are increasingly recognized as key players in the pathogenesis of proteinuria in primary and secondary glomerular disorders. The lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) is a key determinant of podocyte injury and a known off target of the anti-CD20 antibody rituximab (RTX). The current study investigates the role of sphingolipids in radiation-induced podocytopathy. After a single dose of radiation (8 Gy), several ceramide species were significantly elevated. In particular, C16:00, C24:00, and C24:1 ceramides were the most abundant ceramide species detected. These changes were paralleled by a time-dependent drop in SMPDL3b protein, sphingosine, and sphingosine-1-phosphate levels. Interestingly, SMPDL3b-overexpressing podocytes had higher basal levels of sphingosine-1-phosphate and maintained basal ceramide levels after irradiation. Morphologically, irradiated podocytes demonstrated loss of filopodia and remodeling of cortical actin. Furthermore, the actin binding protein ezrin relocated from the plasma membrane to the cytosol as early as 2 h after radiation. In contrast, SMPDL3b overexpressing podocytes were protected from radiation-induced cytoskeletal remodeling. Treatment with RTX before radiation exposure partially protected podocytes from SMPDL3b loss, cytoskeletal remodeling, and caspase 3 cleavage. Our results demonstrate that radiation injury induces early cytoskeletal remodeling, down-regulation of SMPDL3b, and elevation of cellular ceramide levels. Overexpression of SMPDL3b and pretreatment with RTX confer a radioprotective effect in cultured podocytes. These findings indicate a potential role for SMPDL3b and RTX in radiation-induced podocytopathy.-Ahmad, A., Mitrofanova, A., Bielawski, J., Yang, Y., Marples, B., Fornoni, A., Zeidan, Y. H. Sphingomyelinase-like phosphodiesterase 3b mediates radiation-induced damage of renal podocytes.

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

“…In the pathogenesis of Wilson disease and heart disease, aSMase and ceramide accumulation have been shown to be involved in apoptosis of various causes (87)(88)(89)(90). Two studies indicated that ceramide, as a downstream product of activated aSMase, is crucially involved in the apoptosis of pulmonary epithelial cells and renal podocytes, indicating that ceramide perhaps not only mediates acute cellular stress but also participates in progressive tissue degeneration (91,92). In particular, the direct regulatory effect of aSMase and ceramide on mitochondrial dysfunction was related to suppression of the mitochondrial respiratory chain (92).…”

“…Two studies indicated that ceramide, as a downstream product of activated aSMase, is crucially involved in the apoptosis of pulmonary epithelial cells and renal podocytes, indicating that ceramide perhaps not only mediates acute cellular stress but also participates in progressive tissue degeneration (91,92). In particular, the direct regulatory effect of aSMase and ceramide on mitochondrial dysfunction was related to suppression of the mitochondrial respiratory chain (92). In renal tubular epithelial cells, it has been suggested that the addition of troxerutin increases the SM content through galactose-3-O-sulfotransferase-1 and sphingomyelin phosphodiesterase-1, which are involved in SM metabolism (94), and inhibits the expression of SMase, thereby reducing ceramide and lipotoxicity.…”

Urinary excretion of sphingomyelinase phosphodiesterase acid‐like 3b in children with intractable nephrotic syndrome

“…2 Furthermore, SMPDL-3b was recently identified as a key molecule in proteinuric glomerular diseases such as focal segmental glomerulosclerosis (FSGS), 1,3,4 diabetic nephropathy 5 and radiation-induced glomerulopathy. 6 Importantly, decreased expression of SMPDL-3b has been reported in podocytes from patients with post-transplant recurrent FSGS, due to alterations in the podocyte cytoskeleton after exposure to sera from patients with FSGS. 1 Furthermore, pretreatment with rituximab (RTX), a specific antibody to human CD20, had a protective effect against such unfavorable alterations in podocytes.…”

“…SMPDL‐3b has been reported to be involved in macrophage‐related innate immunity, as well as in regulation of the podocyte cytoskeleton . Furthermore, SMPDL‐3b was recently identified as a key molecule in proteinuric glomerular diseases such as focal segmental glomerulosclerosis (FSGS), diabetic nephropathy and radiation‐induced glomerulopathy . Importantly, decreased expression of SMPDL‐3b has been reported in podocytes from patients with post‐transplant recurrent FSGS, due to alterations in the podocyte cytoskeleton after exposure to sera from patients with FSGS .…”

“…Furthermore, pretreatment with rituximab (RTX), a specific antibody to human CD20, had a protective effect against such unfavorable alterations in podocytes . Recent studies have suggested that the anti‐proteinuric effect of RTX observed in clinical and experimental settings is partly due to a direct effect on SMPDL‐3b . The implications of urinary SMPDL‐3b expression in children with intractable nephrotic syndrome (NS), however, remain to be studied.…”