Quantifying podocyte depletion: theoretical and practical considerations

Puelles, Victor G.; Bertram, John F.; Moeller, Marcus J.

doi:10.1007/s00441-017-2630-z

Cited by 17 publications

(20 citation statements)

References 44 publications

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“…Why is the methodology to measure podocyte number important in this debate? [ 47 – 49 ] Methods that rely on the podocyte mean derived by summing podocyte number (numerator) in a fixed number of glomeruli (denominator) regardless of their degree of injury, will underestimate podocyte replacement in individual glomeruli because of the focal nature of disease in healthy aging. In the current study, we make two important observations in this context.…”

Section: Discussionmentioning

confidence: 99%

Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

Kaverina

Eng

Miner

et al. 2020

Aging

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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.

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Section: Discussionmentioning

confidence: 99%

Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

Kaverina

Eng

Miner

et al. 2020

Aging

View full text Add to dashboard Cite

show abstract

“…Others have shown that the use of 4 μm sections, particularly when observing glomeruli, is problematic due the relatively small sampling of the ≅80 μm glomerulus (4μm = 5%), and the inherent heterogeneity in glomerular size both normally and in disease 20 . In the current study, we utilized 20 μm sections and optical sectioning by confocal microscopy.…”

Section: Discussionmentioning

confidence: 99%

Detection of renin lineage cell transdifferentiation to podocytes in the kidney glomerulus with dual lineage tracing

Eng

Kaverina

Schneider

et al. 2018

Kidney International

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Understanding of cellular transdifferentiation is limited by the technical inability to track multiple lineages in vivo. To overcome this we developed a new tool to simultaneously fate map two distinct cell types in the kidney, and genetically test whether cells of renin lineage (CoRL) can transdifferentiate to a podocyte fate. Ren1cCreER/tdTomato/Nphs1-FLPo/FRT-EGFP mice (CoRL-PODO mice) were generated by crossing Ren1c-CreER/tdTomato CoRL reporter mice with Nphs1-FLPo/FRT-EGFP podocyte reporter mice. Following tamoxifen administration in these animals, CoRL were labeled with red fluorescence (tdTomato) and co-localized with renin. Podocytes were labeled green (enhanced green fluorescent protein) and co-localized with nephrin. Following podocyte loss by nephrotoxic antibody and subsequent enalapril-enhanced partial replacement, tdTomato-EGFP-labeled CoRL were detected as yellow-colored cells in a subset of glomerular tufts, without the use of antibodies. Co-localization with podocin indicated that these cells are podocytes, derived from CoRL origin. Thus, our novel study shows that two distinct cell types can be simultaneously labeled in the mouse kidney and provide strong genetic evidence in vivo that lost podocytes can be replaced in part by CoRL.

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“…Podocyte depletion indices were assessed by the Weibel and Gomez method 67 validated by White and Bilous 68 in the kidney. This is one of the preferred methods to determine podocyte depletion parameters when limited tissue is available 69,70 . Briefly, 1-μm-thick paraffin sections were cut and stained with anti-p57, anti-SNP, and anti-CD44 antibodies and conjugated with AF488, AF594, and AF647, respectively.…”

Section: Methodsmentioning

confidence: 99%

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

et al. 2019

Self Cite

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The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and β1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.

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Quantifying podocyte depletion: theoretical and practical considerations

Cited by 17 publications

References 44 publications

Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

Detection of renin lineage cell transdifferentiation to podocytes in the kidney glomerulus with dual lineage tracing

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

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