Mechanisms of the Renoprotective Properties of Zinc Supplementation in Mouse Models of Chronic Kidney Disease

补锌对慢性肾病小鼠模型肾脏保护作用的机制

• 批准号: 10503782
• 负责人: Clintoria Richards Williams
• 金额: $ 48.57万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-31 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503782
• 关键词: Antihypertensive Agents; Attenuated; Biological Availability; Blood Pressure; Calcineurin inhibitor; Carrier Proteins; Cells; Chronic Kidney Failure; Data; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Diet; Disease Progression; Disease model; Distal convoluted renal tubule structure; Early Intervention; Equilibrium; Excretory function; Exhibits; FDA approved; Goals; Health; Homeostasis; Hydroxychloroquine; Hypertension; Impairment; In Vitro; Intervention; Ionophores; Kidney; Knowledge; Link; Maintenance; Modeling; Molecular; Mus; Nuclear; Outcome; Pathway interactions; Patients; Physiological; Plasma; Populations at Risk; Property; Public Health; Publishing; Renal Hypertension; Renal function; Reporting; Resistance; Resistant Hypertension; Role; SLC12A3 gene; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Therapeutic Effect; Translations; Transplant Recipients; Work; Zinc deficiency; Zinc supplementation; blood pressure elevation; blood pressure regulation; combat; epithelial Na+ channel; inhibitor; insight; mouse model; novel; novel strategies; novel therapeutic intervention; preclinical study; prevent; renal damage; urinary; wasting

PROJECT SUMMARY/ABSTRACT Up to 90% of chronic kidney disease (CKD) patients exhibit hypertension, which accelerates kidney damage and kidney function decline. Despite many anti-hypertensive drugs, blood pressure (BP) often remains uncontrolled. In fact, CKD is the strongest predictor of treatment-resistant hypertension. Critically, CKD is a silent killer: An alarming 96% of those with early, asymptomatic CKD are unaware of their condition. Thus, there is pressing need for novel strategies to combat the detrimental cycle of hypertension and kidney damage. Importantly, Zn deficiency has been linked to impaired renal Na+ excretory function, hypertension, and kidney damage. Notably, the renal sodium chloride cotransporter (NCC), a critical determinant of whole-body Na+ balance and BP homeostasis in the distal convoluted tubules (DCT), has been shown to be Zn-sensitive. Specifically, Zn-deficient mice showed upregulated NCC, enhanced Na+ reabsorption, and elevated BP; but Zn repletion reversed these derangements. However, other reports show that, as CKD progresses through stages, fractional urinary excretion of Zn increased as plasma levels of Zn decreased, with a sharp increase in urinary excretion of Zn at stage 3. Critically, this is before most patients are even diagnosed. Thus, Zn supplementation may be effective to restore BP homeostasis in early stages of CKD; but its effects may be limited if later-stage kidney damage diminishes Zn bioavailability. Therefore, there is an urgent need to fill the critical gaps in therapeutic knowledge of Zn supplementation and mechanistic knowledge of the Zn-sensitive renal pathways. The overall objectives of this proposal are to (i) assess Zn supplementation as a therapy to restore BP regulation in early and late stages of CKD, and (ii) identify the mechanisms of Zn-sensitive DCT Na+ handling, with the ultimate goal to identify novel therapeutic approaches effective for all stages of CKD. This will be done via these 3 Aims: Aim 1. Assess efficacy of Zn to delay hypertension and disease progression in early CKD: Calcineurin inhibitor-treated mice and Akita diabetic nephropathy mice will serve as CKD models to rigorously test the novel working hypothesis that Zn supplementation in early CKD restores Zn homeostasis, limits renal Na+ reabsorption, reduces hypertension, and slows CKD progression. Aim 2. Assess efficacy of Zn plus a Zn ionophore to restore Zn homeostasis, renal Na+ excretion, and BP regulation in late-stage CKD: The same mouse models at later stages will test the working hypothesis that Zn supplementation with a Zn ionophore, promotes Zn bioavailability to overcome Zn wasting, stimulate renal Na+ excretion, and restore BP homeostasis - despite late-stage kidney damage. Aim 3. Establish signaling molecules underlying Zn sensitivity of DCT-dependent Na+ handling and BP homeostasis: Developed mouse models and mouse DCT cells will be used to identify Zn-sensitive signaling molecules that limit DCT Na+ reabsorption pathways and promote Na+ balance and BP homeostasis.

项目摘要/摘要 多达90％的慢性肾脏病（CKD）患者表现出高血压，这加速了肾脏损伤 和肾功能下降。尽管有许多抗高血压药，但血压（BP）经常仍然存在 不受控制。实际上，CKD是耐治疗高血压的最强预测指标。至关重要的是，CKD是 沉默的杀手：早期无症状CKD的人中有96％的人没有意识到自己的状况。因此， 迫切需要采取新型策略来应对高血压和肾脏的有害周期 损害。重要的是，Zn缺乏症与肾脏Na+排泄功能受损，高血压， 和肾脏伤害。值得注意的是，肾氯化钠共转运蛋白（NCC），一个关键决定因素 全身Na+平衡和BP稳态远端小管（DCT）已被证明为 Zn敏感。具体而言，缺陷Zn的小鼠表现出上调的NCC，Na+重吸收增强，并且 bp升高；但是Zn的补充扭转了这些危险。但是，其他报告表明，作为CKD 通过阶段进展，随着锌的血浆水平降低，锌的分数排泄增加， 在第3阶段Zn的尿液排泄急剧增加。至关重要的是，大多数患者甚至是在大多数患者之前 诊断。因此，补充锌可能有效地恢复了CKD早期的BP稳态。 但是，如果后期肾脏损伤会减少锌生物利用度，则其影响可能会受到限制。 因此，迫切需要填补补充锌的治疗知识的关键空白 和对Zn敏感肾脏途径的机械知识。该提议的总体目标是 （i）评估补充锌作为恢复CKD早期和晚期恢复BP调节的疗法， （ii）确定对Zn敏感DCT Na+处理的机制，其最终目标是识别新颖 治疗方法对CKD的所有阶段有效。这将通过这三个目标完成： AIM 1。评估Zn在早期CKD中延迟高血压和疾病进展的功效： 钙调神经蛋白抑制剂治疗的小鼠和Akita糖尿病性肾病小鼠将用作CKD模型 严格测试新的工作假设，即早期CKD中补充锌会恢复Zn稳态， 限制肾脏Na+可吸收，减少高血压，并减慢CKD的进展。 AIM 2。评估Zn和Zn离子载体的功效以恢复Zn稳态，肾脏Na+排泄， 后期CKD中的BP调节：以后的同一鼠标模型将测试工作 假设用锌离子载体补充锌，促进了锌生物利用度以克服Zn 尽管后期肾脏受损，浪费，刺激肾脏Na+排泄并恢复BP稳态。 AIM 3。建立依赖DCT依赖性Na+处理的Zn灵敏度的信号分子和 BP稳态：开发的鼠标模型和小鼠DCT细胞将用于识别Zn敏感 限制DCT Na+吸收途径并促进Na+平衡和BP的信号分子 稳态。