Kir5.1 x Kir4.1

更新于：2025-01-23

基本信息

关联

项与 Kir5.1 x Kir4.1 相关的药物

VU6036720

靶点

Kir4.1 x Kir5.1

作用机制

Kir4.1 抑制剂 [+1]

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症

水肿 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Kir5.1 x Kir4.1 相关的临床结果

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100 项与 Kir5.1 x Kir4.1 相关的转化医学

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0 项与 Kir5.1 x Kir4.1 相关的专利（医药）

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115

项与 Kir5.1 x Kir4.1 相关的文献（医药）

2024-11-01·Journal of the American Society of Nephrology

Angiotensin II–Type-1a Receptor and Renal K+ Wasting during Overnight Low-Na+ Intake

Article

作者: Wang, Wen-Hui ; Zheng, Jun-Ya ; Duan, Xin-Peng ; Xiao, Yu ; Lin, Dao-Hong ; Zhang, Cheng-Biao

Key Points

Angiotensin II–type-1a-receptor in the distal convoluted tubule (DCT) plays a role in regulating sodium transport in the DCT.

Angiotensin II–type-1a-receptor in the DCT plays a role in maintaining potassium homeostasis during sodium restriction.

BackgroundChronic angiotensin II perfusion stimulates Kir4.1/Kir5.1 of the distal convoluted tubule (DCT) via angiotensin II–type-1a-receptor (AT1aR), and low‐sodium intake also stimulates Kir4.1/Kir5.1. However, the role of AT1aR in mediating the effect of low salt on Kir4.1/Kir5.1 is not explored.MethodsWe used the patch-clamp technique to examine Kir4.1/Kir5.1 activity of the DCT, employed immunoblotting to examine Na-Cl cotransporter (NCC) expression/activity, and used the in vivo perfusion technique to measure renal Na+ and renal K+ excretion in control, kidney tubule–specific–AT1aR-knockout mice (Ks-AT1aR-KO) and DCT-specific–AT1aR-knockout mice (DCT-AT1aR-KO).ResultsAngiotensin II acutely stimulated the 40-pS-K+ channel (Kir4.1/Kir5.1-heterotetramer) and increased whole-cell Kir4.1/Kir5.1-mediated K+ currents and the negativity of DCT membrane potential only in late DCT2 but not in early DCT. Acute angiotensin II increased thiazide-induced renal Na+ excretion (ENa). The effect of angiotensin II on Kir4.1/Kir5.1 and hydrochlorothiazide-induced ENa was absent in Ks-AT1aR-KO mice. Overnight low-salt intake stimulated the expression of Agtr1a mRNA in DCT, increased whole-cell Kir4.1/Kir5.1-mediated K+ currents in late DCT, hyperpolarized late DCT membrane, augmented the expression of phosphor-Na-Cl-cotransporter, and enhanced thiazide-induced renal-ENa in the control mice. However, the effect of overnight low-salt intake on Kir4.1/Kir5.1 activity, DCT membrane potential, and NCC activity/expression was abolished in DCT-AT1aR-KO or Ks-AT1aR-KO mice. Overnight low-salt intake had no effect on baseline renal K+ excretion (EK) and plasma K+ concentrations in the control mice, but it increased baseline renal-EK and decreased plasma K+ concentrations in DCT-AT1aR-KO or in Ks-AT1aR-KO mice.ConclusionsAcute angiotensin II or overnight low-salt intake stimulated Kir4.1/Kir5.1 in late DCT, and AT1aR was responsible for acute angiotensin II or overnight low-salt intake–induced stimulation of Kir4.1/Kir5.1 and NCC. AT1aR of the DCT plays a role in maintaining adequate baseline renal-EK and plasma K+ concentrations during overnight low-salt intake.

2024-09-01·Journal of the American Society of Nephrology

mTORc2 in Distal Convoluted Tubule and Renal K+ Excretion during High Dietary K+ Intake

Article

作者: Zheng, Jun-Ya ; Duan, Xin-Peng ; Lin, Dao-Hong ; Wang, Ming-Xiao ; Chowdhury, Tanzina ; Zhang, Chengbiao ; Jiang, Shao-Peng ; Wang, Wen-Hui

Key Points

High K stimulates mechanistic target of rapamycin complex 2 (mTORc2) in the distal convoluted tubule (DCT).

Inhibition of mTORc2 decreased the basolateral Kir4.1/Kir5.1 and Na-Cl cotransporter in the DCT.

Inhibition of mTORc2 of the DCT compromised kidneys' ability to excrete potassium during high K intake.

BackgroundRenal mechanistic target of rapamycin complex 2 (mTORc2) plays a role in regulating renal K+ excretion (renal-EK) and K+ homeostasis. Inhibition of renal mTORc2 causes hyperkalemia due to suppressing epithelial Na+ channel and renal outer medullary K+ (Kir1.1) in the collecting duct. We now explore whether mTORc2 of distal convoluted tubules (DCTs) regulates basolateral Kir4.1/Kir5.1, Na-Cl cotransporter (NCC), and renal-EK.MethodsWe used patch-clamp technique to examine basolateral Kir4.1/Kir5.1 in early DCT, immunoblotting, and immunofluorescence to examine NCC expression and in vivo measurement of urinary K+ excretion to determine baseline renal-EK in mice treated with an mTORc2 inhibitor and in DCT-specific rapamycin-insensitive companion of mTOR knockout (DCT-RICTOR-KO) mice.ResultsInhibition of mTORc2 with AZD8055 abolished high-K+–induced inhibition of Kir4.1/Kir5.1 in DCT, high potassium–induced depolarization of the DCT membrane, and high potassium–induced suppression of phosphorylated Na-Cl cotransporter (pNCC) expression. AZD8055 stimulated the 40-pS inwardly rectifying K+ channel (Kir4.1/Kir5.1-heterotetramer) in early DCT in the mice on overnight high potassium intake; this effect was absent in the presence of protein kinase C inhibitors, which also stimulated Kir4.1/Kir5.1. AZD8055 treatment decreased renal-EK in animals on overnight high-potassium diet. Deletion of RICTOR in the DCT increased the Kir4.1/Kir5.1-mediated K+ currents, hyperpolarized the DCT membrane, and increased the expression of pWNK4 and pNCC. Renal-EK was lower and plasma K+ was higher in DCT-RICTOR-KO mice than corresponding control mice. In addition, overnight high-potassium diet did not inhibit Kir4.1/Kir5.1 activity in the DCT and failed to inhibit the expression of pNCC in DCT-RICTOR-KO mice. Overnight high potassium intake stimulated renal-EK in control mice, but this effect was attenuated in DCT-RICTOR-KO mice. Thus, overnight high potassium intake induced hyperkalemia in DCT-RICTOR-KO mice but not in control mice.ConclusionsmTORc2 of the DCT inhibits Kir4.1/Kir5.1 activity and NCC expression and stimulates renal-EK during high potassium intake.

2024-08-01·Acta Physiologica

Role of calcineurin in regulating renal potassium (K⁺) excretion: Mechanisms of calcineurin inhibitor‐induced hyperkalemia

Review

作者: Lin, Dao-Hong ; Duan, Xin-Peng ; Zhang, Cheng-Biao ; Wang, Wen-Hui

AbstractCalcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium‐dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na+ and K+ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting‐related‐receptor‐with‐A‐type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide‐sensitive NaCl‐cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch‐like‐3/CUL3 E3 ubiquitin–ligase complex, which is responsible for WNK (with‐no‐lysin‐kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K+ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial‐Na+‐channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin‐mediated regulation of transepithelial Na+ and K+ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K+ excretion, and induce hyperkalemia.

项与 Kir5.1 x Kir4.1 相关的新闻（医药）

2024-02-19

·生物探索

Nat Chem Biol | 高召兵/郑月明/郭江涛揭示钾通道Kir4.1是具潜力的快速抗抑郁药物靶点

引言重度抑郁症是一种普遍而严重的精神疾病，需要开发新的快速抗抑郁药。基因抑制小鼠侧缰星形细胞内整流钾通道4.1 (Kir4.1)可改善抑郁样表型。然而，Kir4.1仍然是治疗抑郁症的一个难以捉摸的药物靶点。2024年2月14日，中国科学院上海药物研究所高召兵、郑月明及浙江大学郭江涛共同通讯在Nature Chemical Biology (IF 14.8)在线发表题为“Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses”的研究论文，该研究通过高通量筛选发现了一系列Kir4.1抑制剂，Lys05是迄今为止最有效的一种，它有效地抑制了天然的Kir4.1通道，同时对快速起效的抗抑郁药物的既定目标显示出高选择性。冷冻电镜结构结合电生理表征显示Lys05直接结合在Kir4.1的中心腔中。值得注意的是，单剂量的Lys05逆转了kir4.1驱动的抑郁样表型，并在多个典型抑郁症啮齿动物模型中发挥了快速起效(早在1小时)的抗抑郁作用，其疗效与(S)-氯胺酮相当。总的来说，该研究提供了一个概念证明，Kir4.1是一个有希望的快速起效抗抑郁药物的目标。重度抑郁症是最常见和最严重的精神疾病之一，影响全世界约16%的人口，并造成沉重的社会经济负担。传统的药物治疗需要数周或数月才能产生治疗效果，而且对难治性抑郁症患者的疗效很差。最近，谷氨酸N-甲基-D-天冬氨酸(NMDA)受体拮抗剂(S)-氯胺酮被批准用于治疗抑郁症，具有快速起效的特点，这为探索快速起效的药物干预提供了新的思路。然而，安全风险和滥用责任与它的应用有关。迫切需要开发安全有效、起效快的抗抑郁药和新的作用机制。由Kcnj10编码的内纠偏钾通道4.1 (Kir4.1)仅在胶质细胞(星形胶质细胞，少突胶质细胞等)在中枢神经系统。作为星形胶质细胞Kir通道的主要组成部分，Kir4.1主要负责维持星形胶质细胞特有的高K+电导和建立静息膜电位(RMP)。Kir4.1还通过一个被称为“K+空间缓冲”的过程在控制神经元兴奋性方面发挥重要作用，其中Kir4.1摄取局部释放的[K+]o，然后通过电偶联星形细胞网络重新分配K+。星形细胞Kir4.1通道功能障碍，破坏细胞外K+稳态，与一系列神经系统疾病有关，如癫痫、肌萎缩性侧索硬化症和亨廷顿病。此外，依赖于胶质细胞类型和脑区域，与Kir5.1的同源和异四聚体组装相关的复杂表达模式进一步使其生理和病理作用多样化。Lys05作为相对特异性Kir4.1通道抑制剂的鉴定（Credit: Nature Chemical Biology）最近，Kir4.1在侧链(LHb)的上调表达介导的过量K+摄取与抑郁症有关。侧链是大脑的抗奖赏中枢。细胞外K+水平的降低，从而增强了神经元的破裂。病毒将Kir4.1传递到LHb星形胶质细胞足以诱导抑郁样行为。相比之下，敲低Kir4.1蛋白或表达LHb内的显性负性通道可以改善神经元爆发放电和抑郁样表型，揭示了Kir4.1在抑郁症中的潜在治疗价值。此外，LHb神经回路也被发现参与氯胺酮的作用机制，这意味着Kir4.1靶向治疗具有快速起效的潜力。此外，现有的抗抑郁药如选择性血清素再摄取抑制剂和三环抗抑郁药在临床治疗剂量下具有Kir4.1抑制活性，表明Kir4.1通道抑制可能有助于当前的治疗。该研究通过高通量筛选引入了Lys05(1)作为Kir4.1偏好抑制剂，并通过体外和细胞内药理表征验证了其作用。冷冻电镜(cryo-EM)鉴定了Kir4.1与Lys05复合物的结构，在分子水平上提供了Lys05靶向结合的结构证据。研究发现单剂量的Lys05在给药1小时后产生快速起效的抗抑郁作用，不仅对kir4.1驱动的抑郁样表型，而且对各种抑郁动物模型，包括新奇性抑制喂养(NSF)试验、皮质酮诱导的抑郁(CORT)模型和嗅球切除(OBX)模型。因此，广谱抗抑郁反应和Lys05的高靶点特异性支持Kir4.1是开发快速起效抗抑郁药的有希望的靶点。原文链接https://www.nature.com/articles/s41589-024-01555-y责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

临床结果