Kidney Aging Impairs Progenitor and Endocrine Function

肾脏老化损害祖细胞和内分泌功能

• 批准号: 10549835
• 负责人: Stuart James Shankland
• 金额: $ 60.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-11 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549835
• 关键词: Abbreviations; Adult; Age; Aging; Antibodies; Antioxidants; Apoptosis; Attention; Biogenesis; Biology; CDKN2A gene; Cell Cycle; Cell physiology; Cells; Chronic; Complement; Country; Cultured Cells; DNA Damage; Data; Dialysis procedure; Disease; Disease Outcome; Elderly; Enalapril; Endocrine; Epithelial Cells; Erythrocytes; Event; Experimental Models; Female; Focal and Segmental Glomerulosclerosis; Genes; Goals; Grant; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Label; Losartan; LoxP-flanked allele; Messenger RNA; Mitochondria; Mus; Natural regeneration; Parietal; Pathway interactions; Pericytes; Phenotype; Plasma; Population; Process; Production; Proteins; Publishing; RNA; Reactive Oxygen Species; Renal glomerular disease; Renin; Reporter; Reporting; Role; Stimulus; Testing; Time; Transgenic Mice; age related; aged; aging population; cell age; cell regeneration; clinically relevant; complement system; cytokine; density; design; healthy aging; improved; in vivo; innovation; kidney cell; mTOR inhibition; male; mesangial cell; nephrogenesis; older patient; patient population; podocyte; prevent; progenitor; recruit; repaired; response; senescence; stem cell function; stem cells; transcriptome; transcriptome sequencing; transcriptomics; transdifferentiation

Project Summary and Abstract Because the US population is living longer, the impact of advanced age on the kidney is highly clinically relevant. Kidney disease outcomes are worse in the older versus younger patient population s and the elderly comprise the largest group to initiate dialysis annually in the US. Recent attention in the aged kidney has been given to cells of renin lineage because of their two essential functions: their endocrine function of producing the body's supply of renin, and their adult progenitor function as facultative stem cells that transdifferentiate into cell fates that they partially or fully replace, including podocytes. The scope of the problem is that in addition to a decrease in total CoRL density in the aged kidney, both functions are also impaired with advancing age. From the standpoint of glomerular diseases typified by podocyte depletion, reduced CoRL progenitor function limits podocyte regeneration, and therefore repair in the aged kidney. We reported that aged CoRL undergo senescence, apoptosis, and DNA damage, with an increase in complement components and inflammatory cytokines, consistent with a chronic low-grade inflammatory state. Aged CoRL mitochondria have lower biogenesis and energy, but increased reactive oxygen species accumulation. The knowledge gap is identifying the mechanisms that cause these changes to CoRL in aged kidneys. Importantly, our data shows that superimposed glomerular disease compounds the aging phenotype as follows: when podocytes are depleted in young mice in experimental FSGS, the changes to the transcriptome in young CoRL are very similar to the changes in CoRL in the healthy aged kidney without disease. We propose that changes to CoRL in glomerular disease recapitulates and superimposes changes to CoRL in aged kidneys, and that this compounding effect worsens disease outcomes in aged populations. The unmet need is targeting the mechanisms that impair CoRL function in the aged kidney with disease, with the ultimate goal to minimize further injury to the aged kidney. To achieve this, the following specific aims are proposed: (1) Test the hypothesis that senescence impairs the facultative stem cell function of cells of renin lineage (CoRL) during aging. (2) Test the hypothesis that chronic inflammation reduces the endocrine phenotype and function of aged cells of renin lineage. (3) Test the hypothesis that mitochondrial changes in the aged kidney lowers the number of cells of renin lineage. The significance of these studies includes uncovering, for the first time, potential mechanisms whereby age impairs the CoRL endocrine phenotype and function, reduces CoRL progenitor function and lowers CoRL density. In doing so, we will identify targets to modify in disease states in the aged kidney that maintain the CoRL phenotype and enhance their functions. Innovations include identifying changes to a kidney cell (cells of renin lineage) following injury to another kidney cell (podocyte loss) in FSGS that recapitulate the aged phenotype, and that these superimposed changes are very detrimental to the aged kidney.

项目概要和摘要 由于美国人口的寿命越来越长，高龄对肾脏的影响在临床上受到高度重视 相关的。与年轻患者群体和老年人相比，老年患者的肾脏疾病结果更差 是美国每年进行透析的最大群体。最近对老年肾脏的关注已 给予肾素谱系细胞是因为它们有两个基本功能：产生肾素的内分泌功能 体内肾素的供应及其成年祖细胞的功能是兼性干细胞，可转分化为 它们部分或完全取代的细胞命运，包括足细胞。问题的范围是，除了 老年肾脏中总 CoRL 密度下降，这两种功能也会随着年龄的增长而受损。 从以足细胞耗竭为代表的肾小球疾病的角度来看，CoRL祖细胞功能降低 限制足细胞再生，从而限制老化肾脏的修复。我们报道说，老年 CoRL 经历了 衰老、细胞凋亡和 DNA 损伤，伴随补体成分和炎症的增加 细胞因子，与慢性低度炎症状态一致。衰老的 CoRL 线粒体具有较低的 生物发生和能量，但增加活性氧的积累。知识差距正在识别 导致衰老肾脏 CoRL 发生这些变化的机制。重要的是，我们的数据表明 叠加的肾小球疾病使衰老表型复合如下：当足细胞耗尽时 在实验 FSGS 的年轻小鼠中，年轻 CoRL 转录组的变化与 未患病的健康老年肾脏中 CoRL 的变化。我们建议改变肾小球 CoRL 疾病概括并叠加了衰老肾脏中 CoRL 的变化，并且这种复合效应 使老年人的疾病结果恶化。未满足的需求是针对损害的机制 CoRL 在患有疾病的老年肾脏中发挥作用，最终目标是尽量减少对老年人的进一步伤害 肾。为了实现这一目标，提出以下具体目标：（1）检验衰老的假设 在衰老过程中损害肾素谱系细胞 (CoRL) 的兼性干细胞功能。 (2) 检验假设 慢性炎症会降低肾素谱系衰老细胞的内分泌表型和功能。 (3) 测试 假设衰老肾脏中的线粒体变化会降低肾素谱系细胞的数量。 这些研究的意义在于首次揭示了年龄增长的潜在机制 损害 CoRL 内分泌表型和功能，降低 CoRL 祖细胞功能并降低 CoRL 密度。在此过程中，我们将确定改变衰老肾脏疾病状态的目标，以维持 CoRL 表型并增强其功能。创新包括识别肾细胞（肾细胞）的变化 FSGS 中另一个肾细胞损伤（足细胞丢失）后的肾素谱系），再现了衰老过程 表型，这些叠加的变化对衰老的肾脏非常不利。

项目成果

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease.

• DOI: 10.1172/jci156250
• 发表时间: 2022-08-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Pippin, Jeffrey W.;Kaverina, Natalya;Wang, Yuliang;Eng, Diana G.;Zeng, Yuting;Tran, Uyen;Loretz, Carol J.;Chang, Anthony;Akilesh, Shreeram;Poudel, Chetan;Perry, Hannah S.;O'Connor, Christopher;Vaughan, Joshua C.;Bitzer, Markus;Wessely, Oliver;Shankland, Stuart J.
• 通讯作者: Shankland, Stuart J.