A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats.
BACKGROUND
Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients.


METHODS
We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model.


RESULTS
Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes.


CONCLUSIONS
Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD.
Program in Anemia Signaling Research, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Chia Chi
CC
Sun
Valentina
V
Vaja
Shanzhuo
S
Chen
Igor
I
Theurl
Aaron
A
Stepanek
Diane E
DE
Brown
Maria D
MD
Cappellini
Guenter
G
Weiss
Charles C
CC
Hong
Herbert Y
HY
Lin
Jodie L
JL
Babitt
D000225:Adenine / Q000633:toxicity*; D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000378:metabolism; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000890:Anti-Infective Agents; D019485:Bone Morphogenetic Proteins; D064451:Hepcidins; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D007501:Iron; D000225:Adenine
anemia; chronic kidney disease; hepcidin; iron; mouse model