BCL‐XL exerts a protective role against anemia caused by radiation‐induced kidney damage

Abstract

Studies of gene-targeted mice identified the roles of the different prosurvival BCL-2 proteins during embryogenesis. However, little is known about the role(s) of these proteins in adults in 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 c-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 combination with DNA damage-inducing drugs for cancer therapy. Encouragingly, the combination of DNA damage-inducing anti-cancer therapy plus a BCL-XL inhibitor could be tolerated in mice, at least when applied sequentially.

BCL-2 protein family: attractive targets for cancer therapy

“…The loss of BCL-XL causes aberrant apoptosis in postmitotic immature neurons of the developing brain, spinal cord, and dorsal root ganglion, demonstrating its essential role in the survival of these cell populations [28]. Conditional gene deletion studies have shown that in adult mice BCL-XL is critical for erythropoiesis and the survival of certain cell populations in the kidney [29].…”

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…BCL2 is reported to contribute to the development and homeostasis of the mouse epidermis [ 1238 ]. Along similar lines, MCL1 and BCL- X L play roles in the development and homeostasis of several tissues including the myocardium [ 1239 , 1240 ], the CNS [ 148 , 1241 – 1248 ], the hepatic parenchyma [ 298 , 845 , 1249 – 1251 ], vascular endothelium [ 1252 ], thymic epithelium [ 1253 ], as well as the intestinal [ 1254 ], mammary [ 1255 , 1256 ], lung [ 1257 ] and renal [ 277 ] epithelium.…”

“…Similarly, Z-VAD-FMK is ineffective in mouse models of osmotic nephrosis and contrast-induced acute kidney injury [ 276 ], and this may be linked to the ability of Z-VAD-FMK to inhibit CASP8 (and hence promote necroptosis). Finally, acute loss of BCL-X L in all tissues of adult mice, except for hematopoietic cells, caused severe renal tubular degeneration leading to fatal anemia due to the loss of erythropoietin production [ 277 ].…”