MAY 10 th Key Note LectureS
演者紹介・抄録
交感神経活動が食塩過剰摂取による高血圧発症に果たす役割
奈良女子大学 生活環境学部教授 吉本光佐
食塩過剰摂取が高血圧発症に関与している事は、周知の事実である。また、食塩の作用機序として様々な分子メカニズムが解明されて、ナトリウムの体内貯留・体液量の増加や中枢神経系に作用して交感神経を亢進するといった説が示されてきた。しかし食塩過剰摂取が、いつからどのように交感神経を亢進させ高血圧発症までに至るかといった一連の流れは依然として不明である。我々は、ラットの交感神経活動の計測技術を改良し、腎および腰部交感神経活動の長期記録に成功している。ラットの正常血圧状態から、高血圧発症時の腎と腰部交感神経活動の連続記録から、高血圧発症に果たす交感神経活動の役割を検討した。本公演では、アンジオテンシンⅡ-食塩高血圧ラットとDahl食塩感受性高血圧ラットの２種類の食塩過剰摂取による高血圧発症モデルでの昇圧時の交感神経活動の役割を議論したい。
略歴
2005年 奈良女子大学大学院 人間文化研究科 博士後期課程修了博士
2005年 奈良女子大学 大学院人間文化研究科 博士研究員
2006年 ミネソタ大学医学部生理学講座 ポストドクトタルフェロー
208年 カリフォルニア州 サンノゼ 在住
2010年 奈良女子大学 大学院人間文化研究科 博士研究員
2010年 国立循環器病研究センター 研究員
2014年 奈良女子大学研究院 生活環境科学系 助教
2015年 奈良女子大学研究院 生活環境科学系 准教授
2022年 奈良女子大学研究院 生活環境科学系 教授
Non-antigen-dependent CD8T-activation promotes salt-sensitive hypertension
Department of Pharmacology and Toxicology University of Arkansas for Medical Sciences Shengyu Mu
Background: Hypertension is a significant public health problem worldwide, but the pathophysiologic mechanisms are only partially understood. CD8+ T cells (CD8Ts) have been implicated recently in the development of salt-sensitive hypertension. However, the specific mechanisms and key players involved in this process still need to be fully understood. In this study, we used in-vivo models of hypertension and ex-vivo assays of CD8T signaling to investigate the contribution of the P2X7 receptor to CD8T activation and subsequent promotion of sodium retention by the sodium chloride cotransporter (NCC) in the kidney.
Methods: We employed the DOCA/salt and CD8T-adoptive transfer mouse models of hypertension. Wild-type (WT) were used as genetic controls, OT-1 mice were utilized to determine antigen dependency of CD8T-activation, and P2X7-KO mice were studied to define the role of P2X7 in activating CD8Ts and promoting hypertension. Blood pressure was monitored continuously using biotelemetry, and kidneys were obtained at different experimental endpoints for analysis. For activation assays and ATP stimulation, freshly isolated CD8Ts were obtained from sham and hypertensive mice. The role of P2X7 in CD8T activation and promotion of NCC-mediated sodium retention was explored in CD8Ts and mouse distal convoluted tubule cells (DCTs) co-cultures.
Results: We found that OT-1 mice, nonresponsive to common antigens, still developed hypertension and CD8T-activation in response to DOCA/salt treatment, similar to WT mice. Further studies identified the P2X7 receptor on CD8Ts as a possible mediator of this antigen-independent activation of CD8Ts in hypertension. Knockout of the P2X7 receptor prevented calcium influx and cytokine production in CD8Ts. This finding was associated with reduced CD8T-DCT stimulation, reversal of excessive salt retention in DCTs, and attenuated development of salt-sensitive hypertension.
Conclusion: Collectively, our findings suggest a novel mechanism by which CD8Ts are activated in hypertension to exacerbate salt retention. We infer that the P2X7 receptor on CD8Ts may represent a new therapeutic target to attenuate T cell-mediated immunopathology in hypertension.
略歴
Education
Ph.D. (Dr. of Medical Science) University of Tokyo, Tokyo, Japan 2006 - 2011
M.D. TianJin Medical University, TianJin, China 1999 - 2004
Academic Appointments
Associate Professor (with tenure) Department of Pharmacology & Toxicology University of Arkansas for Medical Sciences (UAMS) Little Rock, AR 2022 - Present
Assistant Professor (tenure track) Department of Pharmacology & Toxicology UAMS Little Rock, AR2017 - 2022
Graduate Faculty (GPIBS) UAMS Little Rock, AR 2016 - Present
Assistant Professor (research track) Department of Pharmacology & Toxicology UAMS Little Rock, AR 2013 - 2017
Project Assistant Professor Division of Clinical Epigenetics Research Center for Advanced Science and Technology University of Tokyo, Tokyo, Japan 2012 - 2013
Postdoctoral Fellow Department of Nephrology and Endocrinology School of Medicine, University of Tokyo, Tokyo, Japan 2011 - 2012
Graduate Research Assistant Department of Nephrology and Endocrinology School of Medicine, University of Tokyo, Tokyo, Japan 2007 - 2011