SMPDL3b modulates radiation‐induced DNA damage response in renal podocytes

Abstract

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury.In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

The pathogenesis of Acute Exogenous Lipid Pneumonia based on proteomics

“…All the above proteins were validated, and results indicated that PADI4, IGF2, SMPDL3B, UHRF1, ANXA8, MK167, SLC39A4, LIMD1 and GJA1 were signi cantly upregulated in experimental group compared to the control group. SMPDL3B, ANXA8, MK167, SLC39A4, LIMD1 are mainly related to the occurrence, development and treatment of renal podocyte injury, lung cancer, melanoma, gallbladder cancer, etc [13][14][15][16][17] . However, the function of the PADI4, IGF2, UHRF1, DEFB4 and GJA1 in AELP is unknown and further investigation is needed.…”

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

“…A single dose of radiation increases a variety of ceramide species, decreasing SMPDL3b expression, and decreasing S1P levels in podocytes. The overexpression of SMPDL3b in podocytes prevents these alterations and prevents cytoskeletal rearrangements, reduces reactive oxygen species generation, and improves double-strand break repair associated with radiation treatment, suggesting a protective effect [ 123 , 124 , 125 ].…”

SMPDL3B contributes to gastric adenocarcinoma cells progression by promoting the infiltration of M2 macrophages

“…One of the most extensively researched elements of this molecule is its crucial function in the kidney. The overexpression of SMPDL3B protects versus radiation-induced changes in nuclear ceramide-1-phosphate (C1P) and ceramide levels, which has been linked to a unique role for the protein in DNA damage responses [ 12 ]. SMPDL3B has been shown to be a viable therapeutic target for various disorders and plays a significant role in the onset and progression of a number of diseases.…”