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Time- and dose rate-related effects of internal 177Lu exposure on gene expression in mouse kidney tissue

ABSTRACT: Transcriptomic profiling of normal mouse kidney cortex and medulla following 177Lu irradiation

ORGANISM(S): Mus musculus

PROVIDER: GSE53164 | GEO | 2014/12/17

SECONDARY ACCESSION(S): PRJNA231030

REPOSITORIES: GEO

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Project description:Introduction: Recombinant α1-microglobulin (A1M) is a proposed radioprotector during 177Lu-octreotate treatment of neuroendocrine tumors. Treatment with 177Lu-octreotate is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue while allowing higher absorbed doses to the tumor tissue. However, the mechanisms underlying the protective effects of co-administration of 177Lu-octreotate and A1M are still not fully understood. The aim of this study was to examine the proteomic response of mouse kidneys and bone marrow short time after 177Lu-octreotate and/or A1M administration. Methods: C57/6N mice (n=5/group) were injected with 150 MBq 177Lu-octreotate and/or A1M (5 mg/kg). Corresponding control mice (n=5/group) were injected with saline or the A1M vehicle solution. The animals were killed at 24 hours or 7 days post injection, followed by collection of bone marrow, kidney medulla, and kidney cortex samples at resp. time-points. One of the kidneys from each mouse was used for dosimetric assessment by measuring the 177Lu activity concentration in a gamma counter. Differential protein expression was analyzed with tandem mass spectrometry (LC-MS/MS). Ingenuity Pathway Analysis was then used to simulate affected canonical pathways, upstream regulators, and toxicity functions for identified proteins with |fold change| ≥ 1.5. Results: PHLDA3 was the most prominent radiation responsive protein found in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the 177Lu-octreotate and the 177Lu-octreotate+A1M groups. Several canonical pathways were identified in bone marrow, with the majority found in the 177Lu-octreotate+A1M group. Although toxicity functions related to nephrotoxicity were identified in kidney tissue in all groups, the predicted state (activated or inhibited) of these functions could not be determined. Conclusions: These findings demonstrated a tissue-dependent proteomic response following exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not seem to inhibit the radiation induced expressions, short time after exposure. Long term effects of the combination of A1M and 177Lu-octreotate needs to be further studied.

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Time- and dose rate-related effects of internal 177Lu exposure on gene expression in mouse kidney tissue

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