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中文摘要
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总结 K+平衡的严格调节是正常生理的基础。K+稳态紊乱与 患有多种心血管和肾脏相关疾病远端肾单位(DN),包括 连接小管(CNT)和集合管(CD)是钾离子转运的主要场所。 肾脏,这是必不可少的,以匹配尿钾+排泄不同的饮食钾+摄入量。在这份提案中,我们 在DN中大量表达的机械敏感性Ca 2+渗透性TRPV 4通道是一个关键因素, 肾钾处理的决定因素,能够通过最大钾(BK)刺激流量依赖性K+分泌 通道和抑制H+-K+ ATP酶依赖的K+重吸收。我们找到了大量的支持证据 DN中TRPV 4活性受膳食钾摄入的调节,其功能障碍导致显著的 系统K+平衡失调。TRPV 4-/-小鼠在DN中BK通道活性显著降低, 当饮食中钾摄入量高时,会出现高钾血症。相反,TRPV 4缺失增加了H ~+-K ~+ ATP酶活性和防止低钾血症时,膳食钾摄入量低。总的来说,我们假设 TRPV 4在适应饮食钾方案期间作为生理相关的利尿钾因子 通过刺激BK介导的K+分泌和抑制H+-K+ ATP酶依赖的K+重吸收。 为了解决这一中心假设,我们制定了三个具体目标:SA 1:检查分子和 通过膳食K+摄入调节DN中TRPV 4的信号传导决定因素。SA 2:建立 TRPV 4功能对DN中BK介导的K+分泌的重要性, 其对系统K+平衡的破坏的后果。SA 3:探索以下机制和相关性 TRPV 4对DN中K+重吸收的调节。为了使这个项目取得成果,我们招募了强大的 合作的专业知识和实施一个全面的实验武器库,其中涉及监测TRPV 4 用膜片钳电生理学、细胞内Ca ~(2+)和H ~+-K ~+ ATP酶介导的pH 测量,共聚焦免疫荧光显微镜在啮齿动物和人类的天然DN细胞,平衡 在常规和遗传操作动物中控制膳食K+摄入量的研究。总的来说,我们 期望直接证明机械敏感性TRPV 4通道在DN中的生理相关性, 系统水平,并将定义TRPV 4功能障碍对系统K+的病理生理学影响 体内平衡此外,这将促使开发基于靶向TRPV 4的新策略, 临床环境中危及生命的高钾血症和低钾血症状态。
英文摘要
SUMMARY Tight regulation of K+ balance is fundamental for normal physiology. Disturbed K+ homeostasis is associated with a wide spectrum of cardiovascular- and kidney-related pathologies. The distal nephron (DN), including the connecting tubule (CNT) and the collecting duct (CD), is the major site of controlled potassium transport in the kidney, which is essential to match urinary K+ excretion to varying dietary K+ intake. In this proposal, we posit that the mechanosensitive Ca2+-permeable TRPV4 channel abundantly expressed in the DN is a critical determinant of renal potassium handling capable of stimulating flow-dependent K+ secretion via maxi-K (BK) channel and inhibiting H+-K+ ATPase-dependent K+ reabsorption. We generated abundant supportive evidence that the TRPV4 activity in the DN is regulated by dietary potassium intake with its dysfunction causing significant distortions of systemic K+ balance. TRPV4 -/- mice have a markedly reduced BK channel activity in the DN and develop hyperkalemia when dietary potassium intake is high. On the contrary, TRPV4 deletion augments H+-K+ ATPase activity and protects against hypokalemia when dietary potassium intake is low. Overall, we hypothesize that TRPV4 serves as a physiologically relevant kaliuretic factor during adaptations to dietary potassium regimen by stimulating BK-mediated K+ secretion and inhibiting H+-K+ ATPase-dependent K+ reabsorption. To address this central hypothesis, we developed three specific aims: SA1: Examine molecular and signaling determinants of TRPV4 regulation in the DN by dietary K+ intake. SA2: Establish the importance of TRPV4 function for BK-mediated K+ secretion in the DN and define pathophysiological ramifications of its disruption on systemic K+ balance. SA3: Explore the mechanism and relevance of regulation of K+ reabsorption in the DN by TRPV4. To bring this project to fruition, we recruit strong collaborative expertise and implement a comprehensive experimental arsenal which involves monitoring TRPV4 and BK channels activity with patch clamp electrophysiology, intracellular Ca2+ and H+-K+ ATPase-mediated pH measurements, confocal immunofluorescent microscopy in native DN cells of rodents and humans, balance studies upon manipulation of dietary K+ intake in conventional and genetically manipulated animals. Overall, we expect to directly demonstrate the physiological relevance of mechanosensitive TRPV4 channel in the DN at the systemic level and will define pathophysiological ramifications of TRPV4 dysfunction on systemic K+ homeostasis. Furthermore, this will urge development of novel strategies based on targeting TRPV4 to manage life-threatening states of hyper- and hypokalemia in clinical setting.
期刊论文(7)
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会议论文
TRPV4 deletion protects against hypokalemia during systemic K+ deficiency.
TRPV4 缺失可防止全身缺钾期间出现低钾血症。
DOI: 10.1152/ajprenal.00043.2019
发表时间: 2019
期刊: American journal of physiology. Renal physiology
影响因子: --
作者: [Tomilin,Viktor, Mamenko,Mykola, Zaika,Oleg, Wingo,CharlesS, Pochynyuk,Oleh]
通讯作者: Pochynyuk,Oleh
A peek into Epac physiology in the kidney.
肾脏 Epac 生理学一瞥。
DOI: 10.1152/ajprenal.00373.2019
发表时间: 2019
期刊: American journal of physiology. Renal physiology
影响因子: --
作者: [Tomilin,ViktorN, Pochynyuk,Oleh]
通讯作者: Pochynyuk,Oleh
DOI: 10.1080/19336950.2020.1804153
发表时间: 2020-12
期刊: Channels (Austin, Tex.)
影响因子: --
作者: [Khayyat NH, Tomilin VN, Zaika O, Pochynyuk O]
通讯作者: Pochynyuk O
DOI: 10.14814/phy2.15641
发表时间: 2023-03
期刊: Physiological reports
影响因子: 2.5
作者: []
通讯作者:
Physiology of ClC-K2/b Cl- channel in the collecting duct
Physiology of ClC-K2/b Cl- channel in the collecting duct
Physiology of ClC-K2/b Cl- channel in the collecting duct
Physiology of ClC-K2/b Cl- channel in the collecting duct
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