Integrating novel mechanisms controlling sodium excretion and blood pressure

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PROJECT 1 SUMMARY High salt diets have grown increasingly prevalent in the Western world and contribute to increased risk of cardiovascular disease including hypertension and chronic kidney disease. The renal endothelin system has emerged an important control system for sodium and water excretion and so derangements in this pathway could provide insights for potential new therapeutic approaches. Abnormalities in circadian rhythms are associated with increased risk of a wide range of metabolic, cardiovascular, and other disorders. Furthermore, cardiovascular events are far more prevalent at specific times of day suggesting a circadian contribution of cardiovascular disease. Recent studies have revealed that the peripheral molecular clock regulates water and sodium homeostasis, but the underlying mechanisms are unclear. We recently observed that Bmal1, a circadian-dependent transcription factor, loses its rhythmicity under high salt diet conditions and appears to be regulated by the endothelin (ET) system. Rats lacking a functional ETB receptor have a severely delayed response to an acute salt load that is dependent upon the time of day. Therefore, our goal is to determine the relationship between the ET-1 system and circadian regulation of sodium excretion. Aim 1 is designed to test the hypothesis that ETB receptor activation suppresses Bmal1 to facilitate sodium excretion and account for diurnal renal sodium handling. Aim 2 will test the hypothesis that Bmal1 functions to suppress sodium excretion. We have also uncovered that female rats are protected against the loss of excretory control in a diurnal manner that may be due to differences in sex steroid function. Thus, Aim 3 will test the hypothesis that the balance between effects of testosterone and estrogen effects on vascular ETA receptor function accounts for sex differences in diurnal control of sodium excretion.