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Kidney Aging Impairs Progenitor and Endocrine Function

肾脏老化损害祖细胞和内分泌功能

基本信息

批准号：
10341118
负责人：
Stuart James Shankland
金额：
$ 61.83万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341118
关键词：
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 FRAP1 gene Female Focal Segmental Glomerulosclerosis Genes Goals Grant Impairment In Vitro Inflammation Inflammatory Injury Injury to Kidney Kidney Kidney Diseases Knowledge Label Lead Losartan LoxP-flanked allele Messenger RNA Mitochondria Mus Natural regeneration Parietal 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 male mesangial cell nephrogenesis older patient patient population podocyte prevent progenitor recruit repaired response senescence stem cell function stem cells transcriptome transcriptome sequencing transcriptomics

项目摘要

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.