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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\u2013angiotensin\u2013aldosterone 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\u2013PKA\u2013CREB signaling axis and represents a potential therapeutic target for hypertension and associated renal injury.<\/jats:p>","DOI":"10.3390\/biom16091262","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kcna3 Deficiency Promotes Renin-Associated Hypertension Through Ca2+-Dependent AKT\u2013PKA\u2013CREB Signaling"],"prefix":"10.3390","volume":"16","author":[{"given":"Ye","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Shiyun","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Yuhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Guoqing","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yunlong","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"},{"name":"Basic Medical College, Hebei North University, Zhangjiakou 075000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yingxue","family":"Shi","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Pedro A.","family":"Jose","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA"},{"name":"Division of Kidney Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Zhiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Xing","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Xiaoliang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC), National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model; State Key Laboratory of Respiratory Health and Multimorbidity, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2021). 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