Kcna3 Deficiency Promotes Renin-Associated Hypertension Through Ca²⁺-Dependent AKT-PKA-CREB Signaling

Hypertension is an important risk factor for cardiovascular and renal diseases, yet the mechanisms linking ion channel dysfunction to hypertension remain poorly understood. The voltage-gated potassium channel Kv1.3 (encoded by Kcna3) regulates membrane potential, but its role in the pathogenesis of hypertension remains unclear. In this study, we employed Kcna3 knockout (KO) mice, transcriptomic profiling, and pharmacological inhibition to investigate the role of Kv1.3. Kcna3-deficient mice showed increased blood pressure and renal fibrosis. Transcriptomic profiling showed activation of the renin-angiotensin-aldosterone system (RAAS), with increased renin expression in both Kcna3-deficient mice and Kv1.3 inhibitor-treated cells. Mechanistically, loss of Kv1.3 increased intracellular Ca²⁺ accumulation, activating the phosphoinositide 3-kinase (PI3K)-AKT and protein kinase A (PKA) pathways, leading to cAMP response element binding protein (CREB) phosphorylation and renin upregulation. Pharmacological inhibition of Ca²⁺ signaling or PKA reduced CREB phosphorylation and renin expression, confirming a causal signaling cascade. Thus, Kv1.3 links membrane excitability to RAAS activation via a Ca²⁺-dependent AKT-PKA-CREB signaling axis and represents a potential therapeutic target for hypertension and associated renal injury.