Abstract: SA-PO342

BET Bromodomains Regulate Tubular EMT Program during Renal Fibrogenesis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Tampe, Bjoern, University Medical Center Goettingen, Goettingen, Germany
  • Tampe, Desiree, University Medical Center Goettingen, Goettingen, Germany
  • Mueller, Gerhard A., University Medical Center Goettingen, Goettingen, Germany
  • Zeisberg, Michael, University Medical Center Goettingen, Goettingen, Germany
Background

Kidney fibrosis is associated with loss of functional parenchyma, directly linked to compromised kidney function. Intratubular EMT program of TECs has been shown to contribute to impaired tubular function and correlates with disease progression. In this context, TWIST is considered as a master regulator of EMT. Transcriptional activation is associated with local N-ε-acetylation of lysine side chains towards amino-terminal tails of histone proteins. Members of the bromodomain and dextraterminal (BET) family of bromodomain-containing epigenetic readers associate with acetylated chromatin structures promoting chromatin remodeling, recruitment of proteins involved in transcriptional initiation and activation. It has recently been shown that BRD4 interacts with di-acetylated TWIST to faciliate its recruitment to target gene promoters, initiating EMT program. Because genetically inhibition of TWIST-mediated EMT program in TECs has been shown to faciliate protection of functional parenchyma, we hypothesized that phamacological BET inhibition equally blocks TEC-EMT program.

Methods

In an in vitro system of TEC-EMT, BET inhibition was performed using specific siRNAs and small compounds i-BET151, RVX-208, PFI-1 and (+)-JQ1. Using mice challenged with UUO, the impact of (+)-JQ-1 administration was analyzed by immunostaining and qRT-PCR with regard of renal fibrosis and solute/solvent transporters of functional parenchyma.

Results

Here, we provide evidence that TWIST-induced EMT in TECs requires BRD4. EMT inhibition by targeting BET bromodomains with (+)-JQ1 blocks BRD4/TWIST-mediated transcriptional EMT program, restores altered solute and solvent transporter expression, ultimately associated with attenuation of experimental kidney fibrogenesis. This mechanism is not limited to rodents, we provide evidence that EMT program is also driven by BRD4/TWIST in human cells. Based on existing transcriptional profiling datasets among CKD patients, induction of BRD4/TWIST is associated with intrarenal EMT program (reflected by TWIST1, SNAI1, SNAI2) and kidney fibrosis (reflected by COL1A2 and ACTA2), suggesting that pre-requisits for therapeutical intervention by targeting BRD4/TWIST (e.g. through administration of (+)-JQ1) are also present in humans in principle.

Conclusion

In summary, inhibition of BET bromodomains in the context of EMT represents a potential anti-fibrotic therapy.