Regulation of PTH mRNA stability by the calcimimetic R568 and the phosphorus binder lanthanum carbonate in CKD.
Secondary hyperparathyroidism is characterized by increased parathyroid hormone (PTH) mRNA stability that leads to increased PTH mRNA and serum PTH levels. PTH gene expression is reduced by the calcimimetic R568 and the oral phosphorus binder lanthanum carbonate (La). Changes in PTH mRNA stability are regulated by the binding of trans-acting stabilizing and destabilizing factors to a defined cis element in the PTH mRNA 3'-untranslated region (UTR). Adenosine-uridine (AU)-binding factor 1 (AUF1) is a PTH mRNA-stabilizing protein, and K-homology splicing regulatory protein (KSRP) is a destabilizing protein that targets mRNAs, including PTH mRNA, to degradation by the ribonuclease complex exosome. We now show that KSRP-PTH mRNA binding is decreased in parathyroids from rats with adenine-induced chronic kidney disease (CKD) where PTH mRNA is more stable. KSRP-PTH mRNA binding is increased by treatment with both R568 and La, correlating with decreased PTH gene expression. In vitro degradation assays using transcripts for PTH mRNA and rat parathyroid extracts reproduce the differences in mRNA stability in vivo. Accordingly, PTH mRNA is destabilized in vitro by parathyroid extracts from CKD rats treated with R568 or La compared with parathyroid extracts from untreated CKD rats. This destabilizing effect of R568 and La is dependent on KSRP and the PTH mRNA 3'-UTR. Therefore, the calcimimetic R568 and correction of serum phosphorus by La determine PTH mRNA stability through KSRP-mediated recruitment of a degradation complex to the PTH mRNA, thereby decreasing PTH expression.
Nechama
Morris
M
Minerva Center for Calcium and Bone Metabolism, Hadassah Hebrew Univ. Medical Center, P.O. Box 12000, Jerusalem, Israel 91120.
Ben-Dov
Iddo Z
IZ
Silver
Justin
J
Naveh-Many
Tally
T
D020413:3' Untranslated Regions / Q000187:drug effects; D000225:Adenine; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D006207:Half-Life; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D007811:Lanthanum / Q000494:pharmacology*; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism; D010627:Phenethylamines; D010710:Phosphates / Q000097:blood; D016226:Phosphorus, Dietary; D011437:Propylamines; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D020413:3' Untranslated Regions; D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D010710:Phosphates; D016226:Phosphorus, Dietary; D011437:Propylamines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C119467:lanthanum carbonate; D007811:Lanthanum; D000225:Adenine; D002118:Calcium