Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Lung inflammatory injury and tissue repair (Jul 2023)
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure
Björn Tampe, … , Samy Hakroush, Michael Zeisberg
Björn Tampe, … , Samy Hakroush, Michael Zeisberg
Published April 17, 2018
Citation Information: J Clin Invest. 2018;128(7):3053-3070. https://doi.org/10.1172/JCI89632.
View: Text | PDF
Research Article Nephrology

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure

  • Text
  • PDF
Abstract

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein–signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.

Authors

Björn Tampe, Désirée Tampe, Gunsmaa Nyamsuren, Friederike Klöpper, Gregor Rapp, Anne Kauffels, Thomas Lorf, Elisabeth M. Zeisberg, Gerhard A. Müller, Raghu Kalluri, Samy Hakroush, Michael Zeisberg

×

Figure 3

FK506 disrupts an FKBP12/YY1 transcriptional repressor complex.

Options: View larger image (or click on image) Download as PowerPoint
FK506 disrupts an FKBP12/YY1 transcriptional repressor complex.
(A) TECs...
(A) TECs were exposed to vehicle, indicated concentrations of FK506 (0.02, 0.2, 2, 20, 200 nM, respectively), or equimolar CsA (10 nM). mRNA expression levels of Alk3 were analyzed by qRT-PCR. n = 3 independent experiments. Data are presented as mean ± SD. ***P < 0.001; #P < 0.0001, 1-way ANOVA with Bonferroni’s post hoc analysis. (B and C) Representative photomicrographs of p-Smad1/5/8 complex (p-Smad1/5/8) immunostainings overlayed with differential interference contrast (DIC) are shown. Scale bars: 25 μm. n = 3 independent experiments. Data are presented as mean ± SD. #P < 0.0001, 1-way ANOVA with Bonferroni’s post hoc analysis. (D) Alk3 mRNA expression levels in TECs were analyzed by qRT-PCR after siRNA-mediated knockdown of Fkbp12 (Fkbp12KD), Fkbp25 (Fkbp25KD), Fkbp38 (Fkbp38KD), or Fkbp56 (Fkbp56KD. n = 3 independent experiments. Data are presented as mean ± SD. #P < 0.001, 1-way ANOVA with Bonferroni’s post hoc analysis. (E) As analyzed by coimmunoprecipitation after Alk3 pulldown (IP: Alk3), direct interaction between Fkbp12 and Alk3 was assessed. (F) As analyzed by coimmunoprecipitation after Yy1 pulldown (IP: Yy1), direct interaction between Yy1 and Fkbp12 was assessed. See complete unedited blots in the supplemental material. (G) Alk3 mRNA expression levels were assessed by qRT-PCR after knockdown of either Yy1 (Yy1KD) or Fkbp12 (Fkbp12KD) and exposure to FK506. n = 3 independent experiments. Data are presented as mean ± SD. ***P < 0.001, Student’s t test. (H and I) Representative photomicrographs of p-Smad1/5/8 immunostainings overlayed with DIC are shown. Scale bars: 25 μm. n = 3 independent experiments. Data are presented as mean ± SD. ***P < 0.001, Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts