Targeting ARNT to Attenuate Renal Fibrosis Fibrosis Is an Important Driver of Interstitial Fibrosis

RESEARCH HIGHLIGHTS FIBROSIS Targeting ARNT to attenuate renal fibrosis Fibrosis is an important driver of interstitial fibrosis. By contrast, transcription, whereas depletion of end-stage organ failure and death the CNI ciclosporin, which unlike FKBP12 or YY1 or the addition of modulation in a variety of chronic diseases, FK506 does not form a complex with FK506 induced Alk3 transcription. of the including chronic kidney disease. FK506-binding proteins (FKBPs), Moreover, TEC-specific deletion of However, approaches to attenuate did not attenuate histological renal Yy1 induced Alk3 transcription and FKBP–YY1– the progression of organ fibrosis damage induced by UUO in mice, protected mice from UUO-induced ARNT–ALK3 are limited. Several studies have suggesting that the renoprotective tubular injury and fibrosis. signalling demonstrated efficacy of the effects of FK506 are mediated The researchers then used axis may be calcineurin inhibitor (CNI) FK506 by mechanisms independent of array-based and computational (also known as tacrolimus) in calcineurin inhibition. prediction approaches to identify a promising protecting against acute experimental Using gene set enrichment the transcription factor ARNT as target in organ injury. Now, researchers analysis of transcriptional expression a mediator of Alk3 transcription chronic failure show that low-dose FK506 exerts data, the researchers found that downstream of FKBP12 and YY1. of multiple antifibrotic, renoprotective effects FK506 induced the expression of Small interfering RNA-mediated in a model of renal fibrosis via genes involved in bone morphogenic depletion of ARNT prevented organ systems aryl hydrocarbon receptor nuclear protein (BMP) signalling responses, FK506-induced transcription of translocator (ARNT)-mediated including ALK3, which has Alk3 in vitro. Conversely, disruption transcription of bone morphogenetic previously been shown to mediate of the FKBP12–YY1 complex with protein receptor type 1A the antifibrotic and pro-regenerative low-dose FK506 increased expression (known herein as ALK3). effects of BMP signalling. of Arnt in vitro and in vivo, leading to FK506 is well known for its Pharmacological inhibition of BMP activation of Alk3. immunosuppressive properties signalling blocked the renoprotective To assess the therapeutic potential and is commonly used to lower effects of FK506, supporting a role of targeting the FKBP–YY1–ARNT the risk of rejection in organ for BMP signalling in this process. signalling axis, the researchers transplant recipients. Although FK506 acts by forming a complex used in vivo morpholinos FK506 is nephrotoxic, studies with members of the FKBP family (VMOs) targeting FKBP and YY1. suggest that low doses might induce of adaptor proteins. To identify Administration of these VMOs renoprotective effects through the mechanisms by which FK506 induced expression of intrarenal calcineurin-independent induces ALK3 expression, Tampe ARNT and protected mice from mechanisms. Indeed, in an et al. assessed the effects of depleting UUO-induced renal fibrosis. initial set of experiments, various FKBP family members Similarly, a small-molecule inhibitor Tampe et al. found that on Alk3 transcription in cultured of FKBP12 induced intrarenal Arnt administration of mouse tubular epithelial cells and Alk3 transcription and protected low-dose FK506 to (TECs). Of the FKBPs assessed, mice from tubular injury and mice undergoing only deletion of FKBP12 induced fibrosis. Moreover, this inhibitor also unilateral ureteral Alk3 transcription without the attenuated organ injury in models of obstruction (UUO) need for FK506 supplementation. cardiac and liver fibrosis, prompting reduced chronic Further experiments demonstrated the researchers to speculate that tubular injury and that the effects of FKBP12 on Alk3 modulation of the FKBP–YY1– transcription are mediated ARNT–ALK3 signalling axis may be by direct interactions a promising target in chronic failure between FKBP12 and of multiple organ systems. the transcriptional Susan J. Allison repressor protein ORIGINAL ARTICLE Tampe, B. et al. YY1; the presence Pharmacological induction of hypoxia-inducible of FKBP12–YY1 transcription factor ARNT attenuates chronic kidney complexes correlated failure. J Clin Invest. https://doi.org/10.1172/ JCI89632 (2018) Credit: Lara Crow/Macmillan Publishers Limited with low Alk3 NATURE REVIEWS | NEPHROLOGY VOLUME 14 | SEPTEMBER 2018 | 535 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved..

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