# (PQ12) Targeting SMPDL3b to Prevent Radiation-Induced Nephrotoxicity

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $374,128

## Abstract

PROJECT SUMMARY
Radiation nephropathy (RN) is less common than chemotherapy-induced nephrotoxicity but still represents a
serious late complication after radiation therapies for cancer. RN is irreversible and no effective clinical
treatments exist to prevent RN or ameliorate radiation-associated kidney injury. Podocyte loss, tubular atrophy
and endothelial damage have been linked with RN, but the molecular mechanisms governing RN are not known.
We discovered that the enzyme sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL3b) is an important
regulator of radiation damage in renal podocytes after single dose (SD) radiotherapy (RT). Radiation damage
reduced SMPDL3b expression triggering the cellular relocation of ezrin and a morphological change that altered
podocyte functionality. Treatment with rituximab, which we demonstrated to bind SMPDL3b and to protect
podocyte morphology, reduced SD RT induced RN in C57BL/6 mice but not in our newly-developed conditional
podocyte-specific SMPDL3b knock-out mice. Based on these data we hypothesize that sphingolipids play a vital
role in radiation-induced podocytopathy which governs RN.
The objective is to investigate the mechanistic role of SMPDL3b in renal injury after fractionated low-dose
radiotherapy (F-RT) with concurrent cisplatin (CDDP) as this represents a standard of care for many solid
cancers. Our long-term goal is to discover a molecular-based protective or mitigating strategy for RN, and
potentially chemotherapy-induced nephrotoxicity. We will test our hypothesis with the following three specific
aims using a combined in vivo-in vitro approach:
Aim 1: To determine if SMPDL3b regulates severity and latency of RT-associated kidney injury and functional
RN after clinically-relevant F-RT, CDDP and concurrent F-RT+CDDP. This aim will also explore the role of
SMPDL3b in tissue tolerance for RT retreatment injury, using C57BL/6 mice and our unique SMPDL3b-knockout
and SMPDL3b-inducible mouse models.
Aim 2: To determine the mechanism by which podocyte expression of SMPDL3b affects RT-mediated podocyte
and glomerular endothelial cell (GEC) injury. We hypothesize that SMPDL3b affects RT induced
compartmentalization of podocyte ezrin and affects GECs via altered endothelin-1 (EDN1) and END1 receptor
type A (EDNRA) cross talk. GEC survival after RT will be studied by co-culturing GECs with podocytes lacking
or expressing SMPDL3b.
Aim 3: To determine if targeting sphingolipids prevents RN. We will investigate if protection of SMPDL3b or S1P
will avert long-term functional renal injury in C57BL/6 mice after F-RT, CDDP and F-RT+CDDP. Mechanisms
will be confirmed using our unique SMPDL3b-knockout and SMPDL3b-inducible mouse models.
The findings from these studies will be significant because they offer the potential for molecular-targeted
mitigation for RN, and radiation-associated kidney injury, after RT and combined modality injury.

## Key facts

- **NIH application ID:** 10442691
- **Project number:** 5R01CA227493-05
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** BRIAN MARPLES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,128
- **Award type:** 5
- **Project period:** 2018-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442691

## Citation

> US National Institutes of Health, RePORTER application 10442691, (PQ12) Targeting SMPDL3b to Prevent Radiation-Induced Nephrotoxicity (5R01CA227493-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10442691. Licensed CC0.

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