Perturbation of the circadian clock in chronic diseases involving organ fibrosis

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Abstract

Chronic organ disease is often complicated by fibrosis, the excessive accumulation of extracellular matrix, as a consequence of dysfunctional wound healing responses. Fibrosis progressively distorts tissue architecture and eventually leads to loss of organ function, accounting for up to 45% of deaths in developed countries. Moreover, fibrosis is a major risk factor for tumor development. The few approved therapies aimed at preventing or resolving fibrosis show limited efficacy and safety. One reason for the lack of efficient antifibrotic therapies is the fact that the cell circuits driving the disease biology are still only partially understood. The circadian clock is known to regulate the physiological functions of critical organs, including the liver, kidneys, and lungs. Several experimental and clinical studies have established that circadian disruption plays an important role in the development of chronic diseases across organs involving fibrosis. These include metabolic dysfunction–associated steatotic liver disease, chronic kidney disease, and chronic obstructive pulmonary disease. Here, we provide an overview of the circadian mechanisms that play critical roles in mediating physiological functions in the liver, kidneys, and lungs and whose deregulations could predispose toward development of chronic disease of these organs, leading to fibrosis. We also highlight the possible opportunities of chronotherapy for chronic diseases and discuss future perspectives.

Authors

Atish Mukherji, Pierre-Louis Tharaux, David W. Ray, Thomas F. Baumert