Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes

Patrick Azzam; Marina Francis; Tarek Youssef; Manal Mroueh; Alaa Abou Daher; Assaad A Eid; Alessia Fornoni; Brian Marples; Youssef H Zeidan

doi:10.3389/fmed.2021.732528

Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes

Front Med (Lausanne). 2021 Sep 29:8:732528. doi: 10.3389/fmed.2021.732528. eCollection 2021.

Authors

Patrick Azzam¹, Marina Francis¹, Tarek Youssef¹, Manal Mroueh¹, Alaa Abou Daher¹, Assaad A Eid¹, Alessia Fornoni², Brian Marples³, Youssef H Zeidan^{4

5}

Affiliations

¹ Department of Anatomy, Cell Biology, and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
² Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, FL, United States.
³ Department of Radiation Oncology, University of Rochester, Rochester, NY, United States.
⁴ Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon.
⁵ Baptist Health, Lynn Cancer Institute, Boca Raton, FL, United States.

Abstract

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.

Keywords: NADPH oxidases (NOX); ionizing radiation (IR); nephropathies; podocytes (MeSH: D050199); reactive oxygen species (ROS); smpdl3b; sphingolipids (SLs).