Circadian Clock Regulation of Developmental Time in the Kidney

Abstract

Highlights d Circadian clock oscillations emerge in mouse fetal kidneys prior to birth d Onset of fetal rhythms is timed to a transition in branching rate d Absence of Bmal1, a core clock gene, results in developmental defects d The clock functions as a developmental timer that regulates organogenesis

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

“…It is well-known that tubulointerstitial fibrosis, characterized by excessive extracellular matrix (ECM) deposition, inflammation, and remodeling, is the hallmark of a wide variety of progressive chronic kidney diseases. 18 Here, by generating a mouse line with induced deletion of Bmal1 in adulthood (iKO) to bypass the possible developmental defects in conventional knockouts, 7,19 we confirmed that Bmal1 mediates a major portion of the diurnal variation of urinary volume, and sodium and potassium excretion. Furthermore, we explored the effect of Bmal1 deficiency on renal fibrosis and the underlying mechanisms using a mouse model of unilateral ureteral obstruction (UUO).…”

“…Besides, the current study used mice whose Bmal1 was depleted only during adult‐life, while in the previous study, Clock was prenatally knocked out 25 . Indeed, Dan et al most recently supported that an intact fetal clock is indispensable to proper kidney development and normal kidney function establishment in adults 19 . Thus, potentially adverse effects during embryonic development of Clock gene depletion may also contribute to its unfavorable phenotypes on renal fibrosis.…”

“…15 In the current study, we aimed to investigate the role of Bmal1 in the whole kidneys using adulthood inducible knockout mice to possibly bypass the adverse effect of Bmal1 deficiency during early development and exclude the premature aging impact of the traditional Bmal1 knockout on kidney function. 7,19 We first validated the effect of Bmal1 deficiency on renal waterelectrolyte homeostasis. Functional analysis of the iKO mice showed that postnatal depletion of Bmal1 abrogated the daynight variations for urinary water, sodium and potassium excretion.…”

“…25 Indeed, Dan et al most recently supported that an intact fetal clock is indispensable to proper kidney development and normal kidney function establishment in adults. 19 Thus, potentially adverse effects during embryonic development of Clock gene depletion may also contribute to its unfavorable phenotypes on renal fibrosis. Furthermore, the non-circadian functions of Bmal1 cannot be omitted.…”

“…By generating mice with Bmal1 specifically knocked out in various renal cell types, Firsov and colleagues in succession discovered that Bmal1 in renin‐secreting cells and in podocytes may majorly control urinary excretory rhythms of sodium, potassium, and water, 14,16 while Bmal1 in renal tubular cells control a variety of metabolic processes and are involved in drug disposition 15 . In the current study, we aimed to investigate the role of Bmal1 in the whole kidneys using adulthood inducible knockout mice to possibly bypass the adverse effect of Bmal1 deficiency during early development and exclude the premature aging impact of the traditional Bmal1 knockout on kidney function 7,19 . We first validated the effect of Bmal1 deficiency on renal water‐electrolyte homeostasis.…”