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 由于美国人口寿命延长，高龄对肾脏的影响具有高度的临床意义 切合实际。肾脏疾病的预后在老年患者群体中比在年轻患者群体中更差S和老年人 组成了美国每年发起透析的最大团体。最近人们对老年肾脏的关注已经被 被赋予肾素谱系的细胞，因为它们有两个基本功能：它们产生 体内肾素的供应及其成体祖细胞作为兼性干细胞发挥作用，可转分化为 它们部分或全部取代的细胞命运，包括足细胞。问题的范围是，除了 随着年龄的增长，肾脏的总皮质密度降低，两种功能也受到损害。 从以足细胞耗竭为代表的肾小球疾病的观点来看，COL祖细胞功能降低 限制足细胞再生，因此修复老化的肾脏。我们报道了老年科尔经历了 衰老、细胞凋亡和DNA损伤，补体成分增加和炎症 细胞因子，符合慢性低度炎症状态。衰老的Corl线粒体较低 生物发生和能量，但增加了活性氧物种的积累。知识鸿沟正在显现 导致老年肾脏COL变化的机制。重要的是，我们的数据显示 叠加肾小球疾病使衰老表型复杂化如下：当足细胞耗尽时 在实验性FSGS的幼鼠中，幼年COIL的转录组的变化与 健康老年人肾脏COL的变化。我们认为肾小球中COIL的变化 疾病概括和叠加了老年肾脏COIL的变化，这种复合效应 会恶化老年人口的疾病结局。未得到满足的需求针对的是损害 老年肾脏疾病患者的COIL功能，最终目的是将对老年人的进一步伤害降至最低 肾脏。为了实现这一目标，提出了以下具体目标：(1)检验衰老的假设 在衰老过程中损害肾素细胞系(COIL)的兼性干细胞功能。(2)检验假设 慢性炎症降低了肾素谱系老化细胞的内分泌表型和功能。(3)测试 认为老年肾脏线粒体改变会降低肾素谱系细胞数量的假说。 这些研究的意义包括首次揭示了衰老的潜在机制 损害COIL内分泌表型和功能，降低COL祖细胞功能，降低COL 密度。在这样做的过程中，我们将确定要在老年肾脏的疾病状态中修改的目标，以保持 COIL表型，增强其功能。创新包括识别肾脏细胞(细胞)的变化 肾素谱系)在FSGS中另一个肾细胞损伤(足细胞丢失)，概括了老年人的情况 表型，这些叠加变化是非常不利的老年肾脏。

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.