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.

项目总结/摘要 高达90%的慢性肾脏病（CKD）患者表现出高血压，这会加速肾脏损伤 肾功能下降。尽管有许多抗高血压药物，血压（BP）往往仍然存在。 不受控制事实上，CKD是难治性高血压的最强预测因子。关键是，CKD是一种 沉默的杀手：令人担忧的是，96%的早期无症状CKD患者不知道自己的病情。因此，在本发明中， 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，锌缺乏与肾Na+排泄功能受损、高血压、 和肾损伤值得注意的是，肾氯化钠协同转运蛋白（NCC），一个关键的决定因素， 全身Na+平衡和远曲小管（DCT）中的血压稳态，已被证明是 锌敏感。具体来说，锌缺乏小鼠表现出上调NCC，增强Na+重吸收， 血压升高;但锌补充逆转了这些紊乱。然而，其他报告显示，随着CKD 通过阶段性进展，随着血浆Zn水平的降低， 在第3阶段尿锌排泄急剧增加。关键是，这是在大多数患者甚至 诊断。因此，在CKD早期补充锌可能有效地恢复BP稳态; 但如果后期肾损伤降低了锌的生物利用度，其作用可能是有限的。 因此，迫切需要填补补锌治疗知识的关键空白 和锌敏感性肾通路的机制知识。本建议的总体目标是 （i）评估锌补充作为在CKD早期和晚期恢复BP调节的疗法，和 (ii)确定锌敏感的DCT Na+处理的机制，最终目标是确定新的 对CKD的所有阶段都有效的治疗方法。这将通过这三个目标来实现： 目标1.评估锌延缓早期CKD患者高血压和疾病进展的疗效： 钙调神经磷酸酶处理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中的锌补充恢复锌稳态， 限制肾脏Na+重吸收，降低高血压，减缓CKD进展。 目标2.评估锌加锌离子载体恢复锌稳态、肾Na+排泄的功效， CKD晚期的血压调节：在后期阶段的相同小鼠模型将测试 假设锌离子载体补充锌，促进锌生物利用度，以克服锌 消耗，刺激肾脏Na+排泄，恢复血压稳态-尽管晚期肾损伤。 目标3。建立DCT依赖性Na+处理的Zn敏感性的信号分子， BP稳态：开发的小鼠模型和小鼠DCT细胞将用于鉴定锌敏感性 限制DCT Na+重吸收途径并促进Na+平衡和BP的信号分子 体内平衡