Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

The thiazide-sensitive sodium-chloride-cotransporter (NCC) in the kidney distal convoluted tubule (DCT) plays an essential role sodium and potassium homeostasis. Here, we demonstrate that NCC activity is increased by β2-adrenoceptor agonist salbutamol, a drug prevalently used to treat asthma. Relative β1-adrenergic receptors, β2-adrenergic receptors were greatly enriched mouse DCT cells. In mice, administration of salbutamol phosphorylation (indicating activity) within 30 minutes but also caused hypokalemia, which increases phosphorylation. ex vivo slices isolated tubules, pharmacologically relevant range 0.01-10 μM, effect observed after 15 maintained at 60 minutes. Inhibition inwardly rectifying channel (Kir) 4.1 or downstream with-no-lysine kinases (WNKs) STE20/SPS1-related proline alanine-rich kinase (SPAK) pathway attenuated, did not prevent, salbutamol-induced Salbutamol cAMP mpkDCT cells (model DCT). Phosphoproteomics indicated protein phosphatase 1 (PP1) was key upstream regulator effects. A for PP1 inhibitor (I1) confirmed tubules using inhibitors from I1 knockout mice. On normal high salt diets, infusion systolic blood pressure, this increase normalized thiazide suggesting NCC. Thus, receptor signaling modulates via I1/PP1 WNK-dependent pathways, chronic may be risk factor hypertension.