Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. While both hemodynamic and tubular effects likely participate, most evidence supports a major role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive transporter, NCC, by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule (DCT) to show that DCT cells are especially enriched for β1-adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. As two protein kinases, Ste20p-related Proline Alanine-rich kinase (SPAK) and Oxidative stress responsive 1 (OxSR1), phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect SPAK abundance or its localization in the DCT; instead, we observed a striking activation of OxSR1. We confirmed that SPAK is not required for NCC activation, using SPAK knockout mice. Together, the data provide strong support for a signaling system involving β1- receptors in the DCT that activates NCC, at least in part via OxSR1. The results have implications regarding device- and drug-based treatment of hypertension.