Podocyte Aging: Why and How Getting Old Matters

Shankland, Stuart J.; Wang, Yuliang; Shaw, Andréy S.; Vaughan, Joshua C.; Pippin, Jeffrey W.; Wessely, Oliver

doi:10.1681/asn.2021050614

Cited by 35 publications

(34 citation statements)

References 192 publications

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“…One interesting aspect of the study is interpretation of the data with respect to the health span and life span of podocytes, which are critical to the function and number of aging podocytes ( 25 ). Injecting aPD1ab into aged mice improves the life span (i.e., survival) of podocytes by decreasing several proapoptotic and pyroptosis genes and increasing survival genes.…”

Section: Discussionmentioning

confidence: 99%

“…While a recent study demonstrated a critical role of GSK3b as a mechanism involved in podocyte aging in general ( 24 ), the causes of podocyte changes in aged kidneys are still not completely understood ( 25 ). To gain insights into candidate mechanisms at the transcriptomic level, we recently performed bulk RNA-Seq comparing podocytes from 2- to 3-month-old mice (corresponding to ~20-year-old humans) versus 24-month-old mice (corresponding to humans older than ~70 years) ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

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Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Pippin¹,

Kaverina²,

Wang³

et al. 2022

Journal of Clinical Investigation

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With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Pippin¹,

Kaverina²,

Wang³

et al. 2022

Journal of Clinical Investigation

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“…Hodgin et al (2015) reported that podocyte number per glomerulus decreased from about 550 in children to approximately 400 podocytes per glomerulus in subjects aged in their 80 s (Hodgin et al 2015). A range of mechanisms have been implicated in age-associated podocyte depletion including apoptosis (Lee et al 2004;Tower 2015), pyroptosis (Shankland et al 2021), podocyte detachment (Hodgin et al 2015;Yu et al 2005) and mitotic catastrophe (Lasagni et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…While the present findings clearly illustrate the heightened vulnerability of the ageing kidney to podocyte depletion and the subsequent development of proteinuria and glomerulosclerosis, the mechanisms whereby age increases podocyte susceptibility to disease remain unclear. In their recent timely review on podocyte ageing, Shankland et al (2021) listed senescence, mitochondrial dysfunction, transcriptional changes, sirtuins and reduced autophagy as candidate mechanisms contributing to podocyte ageing (Shankland et al 2021). It is also considered that podocyte ageing is accelerated by age-related comorbidities such as obesity, diabetes and hypertension.…”

Section: Discussionmentioning

confidence: 99%

The ability of remaining glomerular podocytes to adapt to the loss of their neighbours decreases with age

et al. 2022

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Progressive podocyte loss is a feature of healthy ageing. While previous studies have reported age-related changes in podocyte number, density and size and associations with proteinuria and glomerulosclerosis, few studies have examined how the response of remaining podocytes to podocyte depletion changes with age. Mild podocyte depletion was induced in PodCreiDTR mice aged 1, 6, 12 and 18 months via intraperitoneal administration of diphtheria toxin. Control mice received intraperitoneal vehicle. Podometrics, proteinuria and glomerular pathology were assessed, together with podocyte expression of p-rp-S6, a phosphorylation target that represents activity of the mammalian target of rapamycin (mTOR). Podocyte number per glomerulus did not change in control mice in the 18-month time period examined. However, control mice at 18 months had the largest podocytes and the lowest podocyte density. Podocyte depletion at 1, 6 and 12 months resulted in mild albuminuria but no glomerulosclerosis, whereas similar levels of podocyte depletion at 18 months resulted in both albuminuria and glomerulosclerosis. Following podocyte depletion at 6 and 12 months, the number of p-rp-S6 positive podocytes increased significantly, and this was associated with an adaptive increase in podocyte volume. However, at 18 months of age, remaining podocytes were unable to further elevate mTOR expression or undergo hypertrophic adaptation in response to mild podocyte depletion, resulting in marked glomerular pathology. These findings demonstrate the importance of mTORC1-mediated podocyte hypertrophy in both physiological (ageing) and adaptive settings, highlighting a functional limit to podocyte hypertrophy reached under physiological conditions.

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“…Performing bulk RNA sequencing on isolated podocytes from young and aged mice revealed an increase in immune response signaling pathways, gene silencing, and mitogen-activated protein kinase signaling in aged podocytes. 41 , 42 Further investigation of the intersection between aged and injured podocytes may well unravel new potential targets for therapy.…”

Section: Cell-cell and Cell-matrix Signalingmentioning

confidence: 99%

Integrating basic science with translational research: the 13th International Podocyte Conference 2021

Lausecker

Koehler

Fresquet

et al. 2022

Kidney International

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Podocyte Aging: Why and How Getting Old Matters

Cited by 35 publications

References 192 publications

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

The ability of remaining glomerular podocytes to adapt to the loss of their neighbours decreases with age

Integrating basic science with translational research: the 13th International Podocyte Conference 2021

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