Abstract 4161: Protecting Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3b) enhances kidney function and reduces concurrent chemoradiotherapy-induced nephrotoxicity

Abstract

Abstract Background: Cisplatin is a widely used radiosensitizer. Dose-related and cumulative renal insufficiency, including acute renal failure, are the primary dose-limiting toxicities of cisplatin. The lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) and Sphingosine 1-Phosphate Receptor-1 (S1P1) are critical determinants of renal podocyte injury. In the current study, we investigated the functions of SMPDL3b and S1P in cisplatin and radiation-induced renal injury, and the use of rituximab (RTX) to attenuate nephrotoxicity. Material/Methods: Podocytes were incubated for 2 h with S1P (100 nM) or vehicle (2% dodecane/98% ethanol) and irradiated with 0-8 Gy, or podocytes were irradiated (8 Gy) in the presence of RTX (100 mg/ml) or IgG (100 mg/ml). In other experiments, 10-14-week old C57BL/6 mice were given bilateral kidney X-irradiation (4 Gy) using an image-guided small animal arc radiation treatment system (iSMAART), 6mg/kg cisplatin or combined cisplatin plus radiation. Some animals received a single intravenous (IV) injection of rituximab mAb or IgG (50 mg/kg) prior to treatment. Functional kidney parameters and immuno-histopathological assessments of renal damage (e.g. oil red staining, H & E, Periodic Acid-Schiff (PAS) and SMPDL3B expression) were measured post-RT. iSMAART dynamic contrast-enhanced (DCE) imaging was used for estimating glomerular filtration rate 20 weeks post radiation. Results: Exogenous S1P rescued podocytes from concurrent chemoradiotherapy-induced cellular cytoskeletal remodeling, and RTX pretreatment mitigated podocytopathy in vitro. iSMAART dynamic contrast-enhanced (DCE) imaging analysis showed that rituximab pretreatment improved the GFR and kidney function parameters post concurrent chemoradiotherapy. SMPDL3b expression at the protein level and podocyte counts dropped significantly in irradiated kidney post-RT in cisplatin-treated mice. Rituximab pretreatment in cisplatin-treated mice, improved GFR, kidney functional parameters, vascular structure, normalization of pericyte coverage, suppress the development of fibrosis and tubular damage post-irradiation. Conclusion: This study shows that rituximab pretreatment protects mice against concurrent chemoradiation induced kidney injury. SMPDL3b and Sphingosine 1-Phosphate Receptor-1 may be important therapeutic targets for radiation-induced kidney injuries in cancer patients. Citation Format: Anis Ahmad, Alla Mitrofanova, Saba Ansari, Junwei Shi, Yidong Yang, Sandra Merscher, Alessia Fornoni, Youssef Zeidan, Brian Marples. Protecting Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3b) enhances kidney function and reduces concurrent chemoradiotherapy-induced nephrotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4161.