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: 10693949
• 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/10693949
• 关键词: Acceleration; Antihypertensive Agents; Attenuated; Biological Availability; Blood Pressure; Calcineurin inhibitor; Carrier Proteins; Cells; Chronic Kidney Failure; Data; Development; 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; Prediction of Response to Therapy; Property; Public Health; Publishing; Renal Hypertension; Renal function; Reporting; Resistant Hypertension; Role; SLC12A3 gene; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Therapeutic Effect; Translations; Transplant Recipients; Urine; Work; Zinc deficiency; Zinc supplementation; absorption; blood pressure elevation; blood pressure regulation; combat; efficacy evaluation; 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 高达90%的慢性肾脏疾病(CKD)患者表现出高血压，高血压会加速肾脏损害 肾功能下降。尽管有许多降压药，但血压(BP)经常 不受控制。事实上，慢性肾脏病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、无症状的CKD患者并不知道自己的情况。因此， 迫切需要新的策略来对抗高血压和肾脏的有害循环。 损坏。重要的是，锌缺乏与肾脏Na+排泄功能受损、高血压、 和肾脏损伤。值得注意的是，肾脏氯化钠共转运体(NCC)，一个关键的决定因素 已有研究表明，远端曲管(DCT)的全身Na+平衡和BP稳态 对锌敏感。具体地说，缺锌小鼠表现出NCC上调，Na+重吸收增强，以及 血压升高；但锌的补充逆转了这些紊乱。然而，其他报告显示，作为CKD， 分阶段进行，尿锌排泄分数随着血浆锌水平的降低而增加， 在第三阶段尿锌排泄急剧增加。关键的是，这是在大多数患者甚至 诊断出来了。因此，补锌可有效地恢复慢性肾脏病早期的血压稳态； 但如果后期肾脏损伤降低了锌的生物利用率，其影响可能是有限的。 因此，迫切需要填补锌补充剂治疗知识的关键空白。 以及对锌敏感的肾脏通路的机制知识。这项提案的总体目标是 目的：(I)评估补锌作为恢复慢性肾脏病早期和晚期血压调节的治疗方法，以及 (2)确定对锌敏感的DCT钠离子处理机制，最终目标是确定新的 治疗方法对CKD的所有阶段都有效。这将通过以下三个目标来实现： 目的1.评价锌对慢性肾脏病早期高血压和疾病进展的延缓作用： 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 严格检验新的工作假说，即早期CKD补充锌可恢复锌稳态， 限制肾脏对Na+的重吸收，降低高血压，减缓CKD的进展。 目的2.评价锌加锌离子载体恢复锌稳态、肾脏Na+排泄、 晚期慢性肾脏病的血压调节：相同的小鼠模型在后期将测试工作 锌离子载体补充锌可促进锌的生物有效性以克服锌 消瘦，刺激肾脏钠离子排泄，恢复血压平衡--尽管晚期肾脏受损。 目的3.建立依赖DCT的Na+处理对锌敏感的信号分子 血压动态平衡：已开发的小鼠模型和小鼠DCT细胞将用于鉴定锌敏感 限制DCT Na+重吸收途径并促进Na+平衡和BP的信号分子 动态平衡。

项目成果

Hyperphosphatemia and zinc deficiency in chronic kidney disease: unpacking their interconnected roles and nutritional implications.

慢性肾脏病中的高磷血症和锌缺乏：揭示它们相互关联的作用和营养影响。

• DOI: 10.1152/ajprenal.00052.2024
• 发表时间: 2024
• 期刊: American journal of physiology. Renal physiology
• 作者: Williams,ClintoriaR

Zinc Deficiency: A Potential Hidden Driver of the Detrimental Cycle of Chronic Kidney Disease and Hypertension.

缺锌：慢性肾病和高血压有害循环的潜在隐藏驱动因素。

• DOI: 10.34067/kid.0007812021
• 发表时间: 2023
• 期刊: Kidney360
• 作者: Ume,AdakuC;Wenegieme,Tara-Yesomi;Adams,DanielleN;Adesina,SherryE;Williams,ClintoriaR
• 通讯作者: Williams,ClintoriaR