Glucocorticoids and the diurnal rhythm of the thiazide‐sensitive NaCl cotransporter

Abstract

Reabsorbing ~7% of the sodium load, the distal convoluted tubule plays key roles in blood pressure (BP) homeostasis. Here, Na‐Cl co‐transport (NCC) is the major route for apical sodium entry making thiazide diuretics, NCC inhibitors, a mainstay hypertension treatment. Predictive adaptions of sodium excretory rhythms are supported by an intrinsic renal clock, which regulates transporter activity according to physiological need. Peripheral clocks can be influenced by glucocorticoids, which also have a circadian rhythm and we therefore hypothesized that the diurnal rhythm of NCC was regulated by glucocorticoids. C57BL6 mice were kept on a 12h light cycle with subjective day starting at 7am local time. Urine was collected in 12h periods and kidneys harvested at 1am (night) and 1pm (day). Slc12a3 (NCC encoding gene) mRNA and NCC protein abundance were similar between night and day but phosphorylation at threonine 53 was significantly higher at night compared to the day. Both plasma and urinary corticosterone levels were elevated at night. Glucocorticoid inducible leucine zipper (GILZ) and serum and glucocorticoid inducible kinase (SGK1) transcripts were upregulated at 1am compared to 1pm. Chronic corticosterone infusion flattened the corticosterone rhythm at intermediate levels. The diurnal rhythm of T53 phosphorylation was dampened in these mice but not in vehicle‐treated mice. These data indicate that glucocorticoids contribute to the regulation of a diurnal rhythm of NCC phosphorylation. This may be clinically relevant particularly in the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels such as metabolic syndrome and chronic stress.