title: Blockade of Smad signaling by 3'-deoxyadenosine: a mechanism for its anti-fibrotic potential.
abstract: Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3'-Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3'-deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3'-deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3'-deoxyadenosine on the expression of collagens triggered by transforming growth factor-β (TGF-β1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3'-deoxyadenosine suppressed expression of collagens induced by TGF-β1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-β/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3'-Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2α-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3'-deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and α-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3'-deoxyadenosine interferes with the TGF-β and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3'-Deoxyadenosine may be useful for therapeutic intervention in various TGF-β-related fibrotic disorders.
authors: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors: Liubao
authors: L
authors: Gu
authors: Hisashi
authors: H
authors: Johno
authors: Shotaro
authors: S
authors: Nakajima
authors: Hironori
authors: H
authors: Kato
authors: Shuhei
authors: S
authors: Takahashi
authors: Ryohei
authors: R
authors: Katoh
authors: Masanori
authors: M
authors: Kitamura
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002460:Cell Line; D003839:Deoxyadenosines / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D007674:Kidney Diseases / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D003839:Deoxyadenosines; D015852:Eukaryotic Initiation Factor-2; D033703:Nucleoside Transport Proteins; D018047:Receptors, Purinergic P1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C444719:adenosine transporter; C058120:cordycepin