Modulation of radiation‐induced damage of human glomerular endothelial cells by SMPDL3B
Open Access
- 15 April 2020
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 34 (6), 7915-7926
- https://doi.org/10.1096/fj.201902179r
Abstract
The intracellular molecular pathways involved in radiation-induced nephropathy are still poorly understood. Glomerular endothelial cells are key components of the structure and function of the glomerular filtration barrier but little is known about the mechanisms implicated in their injury and repair. The current study establishes the response of immortalized human glomerular endothelial cells (GEnC) to ionizing radiation (IR). We investigated the role of sphingolipids and the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in radiation-induced GEnC damage. After delivering a single dose of radiation, long and very-long-chain ceramide species, and the expression levels of SMPDL3b were elevated. In contrast, levels of ceramide-1-phosphate (C1P) dropped in a time-dependent manner although mRNA and protein levels of ceramide kinase (CERK) remained stable. Treatment with C1P or knocking down SMPDL3b partially restored cell survival and conferred radioprotection. We also report a novel role for the NADPH oxidase enzymes (NOXs), namely NOX1, and NOX-derived reactive oxygen species (ROS) in radiation-induced GEnC damage. Subjecting cultured endothelial cells to radiation was associated with increased NOX activity and superoxide anion generation. Silencing NOX1 using NOX1-specific siRNA mitigated radiation-induced oxidative stress and cellular injury. In addition, we report a novel connection between NOX and SMPDL3b. Treatment with the NOX inhibitor, GKT, decreased radiation-induced cellular injury and restored SMPDL3b basal levels of expression. Our findings indicate the importance of SMPDL3b as a potential therapeutic target in radiation-induced kidney damage.Keywords
Funding Information
- National Institutes of Health (1R01CA227493‐01)
This publication has 49 references indexed in Scilit:
- Ceramide 1-phosphate stimulates proliferation of C2C12 myoblastsBiochimie, 2012
- Activation of mTOR and RhoA is a major mechanism by which ceramide 1-phosphate stimulates macrophage proliferationCellular Signalling, 2011
- AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes*Online Journal of Public Health Informatics, 2010
- Radiation-Associated Kidney InjuryInternational Journal of Radiation Oncology*Biology*Physics, 2010
- Mechanisms of Podocyte Injury in DiabetesDiabetes, 2009
- NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cellsFree Radical Biology & Medicine, 2008
- Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathwayThe Journal of cell biology, 2008
- Ionizing irradiation induces apoptotic damage of salivary gland acinar cells via NADPH oxidase 1-dependent superoxide generationBiochemical and Biophysical Research Communications, 2008
- Nox1-Based NADPH Oxidase Is the Major Source of UVA-Induced Reactive Oxygen Species in Human KeratinocytesJournal of Investigative Dermatology, 2008
- Cell and tissue responses to genotoxic stressThe Journal of Pathology, 2005