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.

项目概要/摘要 高达 90% 的慢性肾脏病 (CKD) 患者患有高血压，这会加速肾脏损伤 和肾功能衰退。尽管使用了许多抗高血压药物，但血压 (BP) 仍常常居高不下。 不受控制。事实上，CKD 是难治性高血压的最强预测因子。关键的是，CKD 是 无声杀手：令人震惊的是，96% 的早期无症状 CKD 患者并不知道自己的病情。因此， 迫切需要新的策略来对抗高血压和肾脏的有害循环 损害。重要的是，缺锌与肾钠排泄功能受损、高血压、 和肾脏损害。值得注意的是，肾氯化钠协同转运蛋白（NCC）是 远曲小管 (DCT) 中的全身 Na+ 平衡和血压稳态已被证明 锌敏感。具体来说，缺锌小鼠表现出 NCC 上调、Na+ 重吸收增强以及 血压升高；但补充锌可以逆转这些紊乱。然而，其他报告显示，随着 CKD 随着阶段的进展，锌的尿排泄分数随着血浆锌水平的降低而增加， 在第 3 阶段，尿中锌的排泄量急剧增加。至关重要的是，这是在大多数患者甚至还没有恢复之前。 确诊。因此，补充锌可能能有效恢复 CKD 早期的血压稳态。 但如果后期肾脏损伤降低了锌的生物利用度，其作用可能会受到限制。 因此，迫切需要填补补锌治疗知识的关键空白 和锌敏感肾通路的机制知识。该提案的总体目标是 (i) 评估补充锌作为一种恢复 CKD 早期和晚期血压调节的疗法，以及 (ii) 确定 Zn 敏感的 DCT Na+ 处理机制，最终目标是识别新的 对 CKD 各个阶段均有效的治疗方法。这将通过以下 3 个目标来实现： 目标 1. 评估锌在早期 CKD 中延缓高血压和疾病进展的功效： 钙调神经磷酸酶抑制剂治疗的小鼠和秋田糖尿病肾病小鼠将作为 CKD 模型 严格测试新的工作假设，即早期 CKD 中补充锌可以恢复锌稳态， 限制肾脏 Na+ 重吸收、降低高血压并减缓 CKD 进展。 目标 2. 评估 Zn 加 Zn 离子载体恢复 Zn 稳态、肾脏 Na+ 排泄、 CKD 晚期的血压调节：相同的小鼠模型将在后期测试其工作情况 假设补充锌离子载体可促进锌的生物利用度，从而克服锌的不足 消耗，刺激肾脏 Na+ 排泄，并恢复血压稳态 - 尽管存在晚期肾脏损伤。 目标 3. 建立 DCT 依赖性 Na+ 处理和 Zn 敏感性的信号分子 血压稳态：开发的小鼠模型和小鼠 DCT 细胞将用于识别锌敏感性 限制 DCT Na+ 重吸收途径并促进 Na+ 平衡和血压的信号分子 体内平衡。