Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1.
Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.
Yeo
Eun-Jin
EJ
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
Ryu
Ji-Hye
JH
Cho
Young-Suk
YS
Chun
Yang-Sook
YS
Huang
L Eric
LE
Kim
Myung-Suk
MS
Park
Jong-Wan
JW
D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000740:Anemia / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009181:Mycoses / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000935:Antifungal Agents; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D004921:Erythropoietin; D000666:Amphotericin B; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat