Human cytomegalovirus inhibits erythropoietin production

TY - JOUR

T1 - Human cytomegalovirus inhibits erythropoietin production

AU - Butler, Lynn M

AU - Dzabic, Mensur

AU - Bakker, Frank

AU - Davoudi, Belghis

AU - Jeffery, Hannah

AU - Religa, Piotr

AU - Bojakowski, Krzysztof

AU - Yaiw, Koon-Chu

AU - Rahbar, Afsar

AU - Söderberg-Naucler, Cecilia

N1 - Copyright © 2014 by the American Society of Nephrology.

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultraviolet-inactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxia-inducible transcription factor (HIF)-1α and HIF2α, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2α mRNA. HIF2α is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2α was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients.

AB - Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultraviolet-inactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxia-inducible transcription factor (HIF)-1α and HIF2α, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2α mRNA. HIF2α is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2α was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients.

KW - Animals

KW - Antibodies, Viral

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Cell Culture Techniques

KW - Cell Hypoxia

KW - Cytomegalovirus

KW - Erythrocyte Count

KW - Erythropoietin

KW - Hemoglobins

KW - Humans

KW - Hypoxia-Inducible Factor 1, alpha Subunit

KW - Immunoglobulin G

KW - Mice

KW - RNA, Messenger

KW - Renal Insufficiency, Chronic

U2 - 10.1681/ASN.2013101125

DO - 10.1681/ASN.2013101125

M3 - SCORING: Journal article

C2 - 24722450

VL - 25

SP - 1669

EP - 1678

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 8

ER -