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

J Clin Invest. 2018 Jul 2;128(7):3053-3070. doi: 10.1172/JCI89632. Epub 2018 Jun 11.

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.

Keywords: Chronic kidney disease; Nephrology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis*
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Cell Line
  • Disease Progression
  • Gene Knockdown Techniques
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Failure, Chronic / drug therapy*
  • Kidney Failure, Chronic / metabolism*
  • Kidney Failure, Chronic / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyrrolidines / pharmacology
  • Signal Transduction / drug effects
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Protein 1A / antagonists & inhibitors
  • Tacrolimus Binding Protein 1A / metabolism
  • YY1 Transcription Factor / antagonists & inhibitors
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism

Substances

  • ARNT protein, human
  • Arnt protein, mouse
  • GPI 1046
  • Pyrrolidines
  • YY1 Transcription Factor
  • YY1 protein, human
  • Yy1 protein, mouse
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • BMPR1A protein, human
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I
  • Tacrolimus Binding Protein 1A
  • Tacrolimus