High dietary sodium causes dyssynchrony of the renal molecular clock in rats

Abstract

Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ET) receptor functions to facilitate Na excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ET-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ET receptors within the renal inner medulla.

Circadian regulation of renal function

“…Unfortunately, we know very little about how various clock genes function in different parts of the kidney. Speed and colleagues recently reported mRNA expression of the major clock genes in cortex and inner medulla of rat kidneys, which follow similar patterns as reported in other tissues [76] (Fig. 4).…”

“…In healthy individuals, there is a diurnal difference in the levels of plasma ET-1, with lower levels observed at night [124], but this is less evident in rats [76] (Fig. 5).…”

“…In kidneys collected from mice and rats (Fig. 5), there appears to be lower levels of ET-1 during the active period [76,125]. A recent study by Johnston et al demonstrated that rats lacking ET B receptor function have an impaired natriuretic response to an acute salt load [126].…”

“…The findings from this study suggest an interaction between endothelin and the circadian clock mechanism to regulate the renal excretion of excess salt. Speed et al expanded on this finding, showing that control rats fed a high salt diet for two weeks exhibited a phase delay of about 5½ hours in the acrophase of Bmal1 , along with a suppression of Cry1 and Per2 , specifically in the inner medulla but not the cortex [76]. In ET B deficient rats, the phase delay in Bmal1 expression was not seen [76], suggesting a possible contribution of clock genes to the delayed natriuretic response seen in the ET B deficient rat model [126].…”

“…Speed et al expanded on this finding, showing that control rats fed a high salt diet for two weeks exhibited a phase delay of about 5½ hours in the acrophase of Bmal1 , along with a suppression of Cry1 and Per2 , specifically in the inner medulla but not the cortex [76]. In ET B deficient rats, the phase delay in Bmal1 expression was not seen [76], suggesting a possible contribution of clock genes to the delayed natriuretic response seen in the ET B deficient rat model [126]. Several studies have examined the influence of Per1 on the endothelin axis in various tissues including the kidney [125,128].…”