Abstract Body: In human and animal hyperaldosteronism-related hypertension, the increased blood volume has been regarded as a primary contributor to hypertension generation. However, increases in arterial contractility (and thus peripheral resistance) are also frequently reported in various hypertension models, including the mineralocorticoid-induced hypertensions such as DOCA-salt hypertension. Moreover, non-renal mechanisms (i.e., direct regulation on the cardiovascular ion channels) of the mineralocorticoid-induced hypertension are reportedly important. Na⁺-leak channel (NALCN) was first cloned as Na⁺/Ca²⁺ channel family in 1999. However, its role in providing background cation conductance and contributing to normal neuronal excitability has been uncovered relatively recently and little is known about the roles of NALCN in cardiovascular system and pathogenesis of hypertension. Here, we show that aldosterone directly upregulates NALCN expression in arterial smooth muscle independent of kidney and contribute to the increases in arterial contractility, thereby contributing to the development of hypertension. Remarkably, mere the transient knockdown of arterial NALCN greatly ameliorated the development of hypertension along with arterial hypercontractility. Moreover, it is very interesting that our findings suggest that NALCN is activated by oxidative stimuli and this activation can be prevented by -gliflozin series SGLT2 inhibitors. From these, we propose that NALCN is a very promising and potent target for the treatment of various hypertensions including mineralocorticoid-related one.