Studies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis, but less is known about the roles of these proteins in adults, including in the response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL-deficiency in erythroid cells. Unexpectedly, the combination of total-body γ-irradiation (TBI) and genetic loss of Bcl-x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combinations with DNA damage-inducing drugs for cancer therapy.

中文翻译：

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BCL-XL对于预防由辐射引起的致命性肾脏损害引起的继发性贫血至关重要

以基因为靶点的小鼠的研究确定了不同的存活前BCL-2蛋白在胚胎发生过程中的作用，但对这些蛋白在成年动物中的作用知之甚少，包括对细胞毒性应激的反应，例如抗癌治疗代理商。我们使用一种策略进行了成年小鼠中BCL-XL的作用研究，在该策略中，先前的骨髓移植允许BCL-XL仅在非造血组织中流失，以防止由红细胞中BCL-XL缺乏引起的贫血。出乎意料的是，全身γ射线照射（TBI）和Bcl - x的遗传损失相结合继发性阻塞性肾病导致的肾小管上皮细胞凋亡导致慢性肾功能衰竭引起继发性贫血。这些发现确定了BCL-XL在成年肾脏中的关键保护作用，并告知BCL-XL抑制剂与DNA损伤诱导药物联合用于癌症治疗的用途。