Reduced Glomerular Progenitors Impair Regeneration in Aged Kidney

肾小球祖细胞减少会损害衰老肾脏的再生

• 批准号: 9329346
• 负责人: Stuart James Shankland
• 金额: $ 47.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329346
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Animal Model; Animals; Antioxidants; Applications Grants; Atrophic; Biology; Cell Aging; Cell Count; Cell Cycle; Cell Cycle Arrest; Cells; Chronic; Cicatrix; Color; Data; Development; Disease; Doxycycline; Elderly; End stage renal failure; Epithelial Cell Proliferation; Epithelial Cells; Etiology; Event; Fibrosis; Focal Segmental Glomerulosclerosis; General Population; Glomerular capsule structure; Goals; Grant; Histologic; Impairment; In Vitro; Incidence; Individual; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Label; Lesion; Light; Literature; Longevity; Maps; Mesenchymal; Modeling; Mus; Natural regeneration; Organ; Oxidative Stress; Parietal; Pathway interactions; Phenotype; Proliferating; Renal function; Renal glomerular disease; Renin; Reporter; Reporting; Retinoids; Role; Secondary to; Sentinel; Sirolimus; Source; Stem cells; Structure; Tamoxifen; Testing; Transgenic Animals; Tubular formation; age effect; age related; aged; aging population; cell age; cell type; density; epidemiologic data; glomerular filtration; glomerulosclerosis; in vivo; inhibitor/antagonist; interstitial; man; middle age; normal aging; novel; novel strategies; oncoprotein p21; podocyte; progenitor; response; self-renewal; senescence; stemness; transdifferentiation; young adult

The general population is living longer, precipitating the need to better understand the effects of aging on organ structure and function. Impaired kidney function is more common in the elderly, and the incidence of ESRD is increasing disproportionately in people > 65yrs. The goal of this grant proposal is to identify novel mechanisms underlying changes in the aging kidney, with a focus on the glomerulus, in particular both glomerular epithelial cell types. Kidney aging is typified by a progressive depletion of podocytes, which directly underlies the development of glomerulosclerosis and reduced kidney function. Terminally differentiated epithelial cells, called podocytes (podo) are unable to adequately proliferate, and therefore cannot replace themselves. Recently a large and compelling literature shows that in young adult and middle-aged kidneys, a subpopulation of neighboring glomerular parietal epithelial cells (PECs) serves as adult podo progenitors. We recently reported that PECs are also affected by aging; characterized by a decrease in total PEC number, with subpopulations of the remaining cells becoming senescent or undergoing mesenchymal transformation. This grant proposal will study the existing problem of age-related podo depletion, but in a completely new context, by addressing major knowledge gaps of PEC progenitors in the aging kidney and their inability to adequately replenish podo. New approaches will include our recently developed dual PEC-podo reporter mice that individually label and lineage trace PECs and podos within the same glomerulus, the use of an inducible PEC progenitor reporter mouse, and the use of primary PECs in culture derived from reporter mice of advanced age. Aim 1 will establish when, and at what rate, PEC progenitor number decreases with advancing age, and will test the hypothesis that progressive cellular senescence is a major cause of reduced PEC progenitors with aging. We will prove that by lowering senescence, PEC progenitor number will be higher, accompanied by higher podocyte density. Aim 2 will prove that the self-renewal of PEC progenitors is lower in aged mice compared to young mice, both chronically over the life span of the animal, and acutely in response to an abrupt decline in podo number in experimental FSGS. Studies will test the hypothesis that aged PEC proliferation is reduced due to de novo increases of the cell cycle inhibitors p21 and p16, and that this is secondary to increased oxidative stress. Aim 3 will show that aged PEC progenitors have a lower transdifferentiation capacity towards a podo fate, and test the hypothesis that this is in part due to the reprogramming of a subset of aged PECs to a mesenchymal fate, thereby limiting their ability to transdifferentiate into adult podos. We anticipate that the results will provide compelling evidence and candidate mechanisms for a new paradigm that the biology and functional roles of PEC progenitors are markedly altered in aged kidneys thus, leading to their inability to replenish podos. These studies will provide evidence for important functional changes in glomerular epithelial cells, which underlie detrimental changes in aged kidneys.

普通人群的寿命越来越长，这促使人们需要更好地了解老龄化对健康的影响