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.

项目摘要和摘要 由于美国人口的寿命更长，因此高级年龄对肾脏的影响在临床上高度高 相关的。在年龄较大的患者人群和老年人中，肾脏疾病的结局较差 组成最大的群体，每年在美国启动透析。老年肾脏的最近关注 由于具有两个基本功能，因此赋予了肾素谱系细胞：它们的内分泌功能 身体的肾素供应及其成年祖细胞作为辅助干细胞的发挥作用 它们部分或完全替代的细胞命运，包括足细胞。问题的范围是 老年肾脏的总CORL密度降低，这两个功能也随着年龄的增长而受损。 从表现出足细胞耗尽的肾小球疾病的角度，降低了CORL祖细胞功能 限制足细胞再生，因此在老年肾脏中修复。我们报告说，老年的Corl经历了 衰老，凋亡和DNA损伤，补体成分和炎症的增加 细胞因子，与慢性低级炎症状态一致。老化的CORL线粒体具有较低的 生物发生和能量，但增加了活性氧的积累。知识差距正在识别 在老年肾脏中导致这些变化的机制。重要的是，我们的数据表明 叠加的肾小球疾病使老化表型化合物如下：耗尽足细胞时 在实验FSG中的年轻小鼠中，年轻Corl转录组的变化与 没有疾病的健康老年肾脏中CORL的变化。我们建议在肾小球中变化 疾病在老年肾脏中概括和叠加对CORL的变化，并且这种复合作用 老年人群的疾病结局恶化。未满足的需求是针对损害机制 CORL在老年肾脏中功能与疾病的功能，最终目标是最大程度地减少对老年人的进一步伤害 肾。为此，提出了以下特定目标：（1）检验衰老的假设 在衰老过程中损害肾素谱系（CORL）细胞的兼性干细胞功能。 （2）检验假设 慢性炎症减少了肾素谱系老化细胞的内分泌表型和功能。 （3）测试 老年肾脏线粒体变化的假设降低了肾素谱系的细胞数量。 这些研究的重要性包括首次揭示了年龄的潜在机制 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。通过这样做，我们将确定在老年肾脏中修改的目标，以维持 CORL表型并增强其功能。创新包括确定对肾细胞的变化（细胞 肾素谱系）在FSG中受伤后的另一个肾细胞（足细胞损失）后，该细胞概括了老化 表型，这些叠加的变化对老年肾脏非常有害。

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.