Therapeutic Targeting of PAS Domain Proteins

Am J Kidney Dis. 2019 Feb;73(2):281-284. doi:10.1053/j.ajkd.2018.08.009. Epub 2018 Oct.

In the Literature Editorial: ARNT as a novel anti-fibrotic target in chronic kidney disease.

Haase VH

Per-Arnt-Sim (PAS) domain proteins are involved in the regulation of cellular responses to environmental stresses such as hypoxia or exposure to polycyclic aromatic hydrocarbons, they furthermore participate in the regulation of circadian rhythm. The therapeutic targeting of PAS domain proteins is likely to impact the clinical practice of Nephrology as multiple compounds that activate hypoxia-inducible factor (HIF) are currently in clinical development for the treatment of renal anemia. HIF, a heterodimeric PAS domain transcription factor, is a central mediator of cellular hypoxia responses and consists of an oxygen-sensitive α-subunit and the constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT), also known as HIF-1β.

In a new preclinical study, published in JCI in April 2018, the research group of Michael Zeisberg at the University of Göttingen has identified the obligatory HIF-α binding partner ARNT as an anti-fibrotic and pro-regenerative inducer of activin-like kinase (ALK) 3 / SMAD signaling. The study suggests that ARNT has therapeutic potential for the treatment of chronic kidney disease (CKD).

In their study Tampe and colleagues hypothesized that molecular pathways which mediate the cytoprotective effects of preconditioning regimens can be therapeutically exploited to promote resistance against progressive fibrotic injury. The authors chose a preconditioning regimen that has been shown to protect multiple organs from progressive injury and is based on the widely-used calcineurin inhibitor FK506, also known as tacrolimus. FK506 is currently undergoing clinical evaluation for organ protection in patients with pulmonary arterial hypertension ( NCT01647945).

(click on title page to view full pdf of accepted manuscript)

link to paper by Tampe and colleagues in JCI, April 2018