Radiation-Induced Nephrotoxicity: Role of Sphingomyelin Phosphodiesterase Acid-like 3b

Radiation nephropathy (RN) can be a significant late complication after radiation therapy (RT) for abdominal and paraspinal tumors. The mechanisms for the development of RN are thought to involve disruption of podocyte function, leading to podocyte cell death and, finally, impaired renal function. This study investigated the mechanistic role of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in regulating podocyte injury and renal function after irradiation. The aim of the study was to investigate the potential linkage between (1) RT-induced renal dysfunction and podocyte SMPDL3b expression and (2) RT-induced podocyte injury and expansion of the glomerular basement membrane (GBM).

SMPDL3b wild-type, siSMPDL3b, and SMPDL3b-overexpressing podocytes were irradiated in cell culture, and cell death was assessed. SMPDL3b wild-type and podocyte-specific SMPDL3b knockout mice were treated with focal bilateral kidney X-irradiation (14 Gy, or 6 × 5 Gy), and podocyte apoptosis, renal function parameters, glomerular filtration rate, glomerular histology, and GBM ultrastructural changes via transmission electron microscopy were assessed.

Following RT treatment, a notable decrease in SMPDL3b expression was observed, accompanied by heightened levels of DNA damage, cytoskeletal alterations, and apoptotic events in cultured podocytes. SMPDL3b overexpression notably prevented DNA damage and apoptosis in cultured podocytes. Additionally, in vivo, RT exposure led to a significant decline in SMPDL3b expression, podocyte count, and renal function while concomitantly elevating GBM thickness, mesangial expansion, and renal fibrosis at the 20-week post-RT. Furthermore, in vivo, rituximab pretreatment before RT prevented SMPDL3b downregulation, podocyte loss, mesangial expansion, GBM expansion, and renal fibrosis and ultimately enhanced renal function post-RT.

Our findings collectively suggest a novel function for SMPDL3b in orchestrating the DNA damage response triggered by radiation. This study proposes that SMPDL3b exerts a regulatory influence on the repair of double-strand breaks within podocytes, consequently averting podocyte loss, GBM expansion, and the onset of RN.