Abstract
Healthy aging is typified by a progressive and absolute loss of podocytes over the lifespan of animals and humans. To test the hypothesis that a subset of glomerular parietal epithelial cell (PEC) progenitors transition to a podocyte fate with aging, dual reporter PEC-rtTA|LC1|tdTomato|Nphs1-FLPo|FRT-EGFP mice were generated. PECs were inducibly labeled with a tdTomato reporter, and podocytes were constitutively labeled with an EGFP reporter. With advancing age (14 and 24 months) glomeruli in the juxta-medullary cortex (JMC) were more severely injured than those in the outer cortex (OC). In aged mice (24m), injured glomeruli with lower podocyte number (41% decrease), showed more PEC migration and differentiation to a podocyte fate than mildly injured or healthy glomeruli. PECs differentiated to a podocyte fate had ultrastructural features of podocytes and co-expressed the podocyte markers podocin, nephrin, p57 and VEGF164, but not markers of mesangial (Perlecan) or endothelial (ERG) cells. PECs differentiated to a podocyte fate did not express CD44, a marker of PEC activation. Taken together, we demonstrate that a subpopulation of PECs differentiate to a podocyte fate predominantly in injured glomeruli in mice of advanced age.
Highlights
Glomerular podocytes are terminally differentiated epithelial cells that cannot proliferate, and are unable to self-renew [1, 2] in states of loss such as healthy aging [3,4,5] and glomerular diseases [6,7,8] any podocyte replacement must rely on local progenitor/stem cells [9]
Podocyte number was lower in the occasional glomerulus with a score of 1 in both outer cortex (OC) and juxta-medullary cortex (JMC) glomeruli in young mice
We used a genetic approach in a dual PEC-Nphs1FLPo/FRT-EGFP podocyte reporter (PODO) reporter mouse [24] to ask if glomerular parietal epithelial cells (PECs) can differentiate to a podocyte fate as podocyte number progressively declines with advancing age
Summary
Glomerular podocytes are terminally differentiated epithelial cells that cannot proliferate, and are unable to self-renew [1, 2] in states of loss such as healthy aging [3,4,5] and glomerular diseases [6,7,8] any podocyte replacement must rely on local progenitor/stem cells [9]. Because of the challenges of studying podocyte replacement in humans, studies have largely relied on lessons learned from animal models. This too has contributed to the “podocyte regeneration/replacement debate”. Studies characterized by glomerular hypertrophy that leads to reduced podocyte density without a loss of podocytes themselves should be questioned as a proper model to study podocyte regeneration. Factors such as mouse age, strain, sex, and the duration of the studies, are potential confounders in this debate. Mouse ages 12, 18, and 24 months correspond to human ages 42.5, 56 and 69 years old respectively [23] and using mice aged 17 months and younger is not considered a model of aging
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