The sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) reabsorbs approximately 7% of the total sodium load and plays a key role in blood pressure control. Thiazide diuretics, which target NCC, are a mainstay of hypertension treatment. NCC activation has a diurnal rhythm, which is dampened by chronic glucocorticoid treatment. Radiotelemetry experiments showed this dampened rhythm is accompanied by non-dipping blood pressure that could be rescued by thiazide treatment¹. The receptor mechanisms through which glucocorticoids activate NCC are not fully elucidated. We have previously demonstrated that chronic GR blockade prevents the corticosterone-induced activation of NCC². This pharmacological approach inhibits the GR expressed in all tissues throughout the body, therefore it is unclear if this is a direct result of GR blockade in the DCT or an indirect effect of GR blockade in other tissues. We hypothesised that GR in DCT contributes directly to the activation of NCC. To test this hypothesis, we generated a novel tamoxifen-inducible DCT-specific GR knock out mouse (DCT-GRKO). This talk will explore our latest data on NCC activation and sodium handling in these DCT-GRKO mice. These data have implications for rhythmic blood pressure control particularly in individuals receiving iatrogenic glucocorticoids or in conditions of chronic stress.