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mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

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mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. / Puelles, Victor G; van der Wolde, James W; Wanner, Nicola; Scheppach, Markus W; Cullen-McEwen, Luise A; Bork, Tillmann; Lindenmeyer, Maja T; Gernhold, Lukas; Wong, Milagros N; Braun, Fabian; Cohen, Clemens D; Kett, Michelle M; Kuppe, Christoph; Kramann, Rafael; Saritas, Turgay; van Roeyen, Claudia R; Moeller, Marcus J; Tribolet, Leon; Rebello, Richard; Sun, Yu By; Li, Jinhua; Müller-Newen, Gerard; Hughson, Michael D; Hoy, Wendy E; Person, Fermin; Wiech, Thorsten; Ricardo, Sharon D; Kerr, Peter G; Denton, Kate M; Furic, Luc; Huber, Tobias B; Nikolic-Paterson, David J; Bertram, John F.

in: JCI INSIGHT, Jahrgang 4, Nr. 18, 19.09.2019.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Puelles, VG, van der Wolde, JW, Wanner, N, Scheppach, MW, Cullen-McEwen, LA, Bork, T, Lindenmeyer, MT, Gernhold, L, Wong, MN, Braun, F, Cohen, CD, Kett, MM, Kuppe, C, Kramann, R, Saritas, T, van Roeyen, CR, Moeller, MJ, Tribolet, L, Rebello, R, Sun, YB, Li, J, Müller-Newen, G, Hughson, MD, Hoy, WE, Person, F, Wiech, T, Ricardo, SD, Kerr, PG, Denton, KM, Furic, L, Huber, TB, Nikolic-Paterson, DJ & Bertram, JF 2019, 'mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans', JCI INSIGHT, Jg. 4, Nr. 18. https://doi.org/10.1172/jci.insight.99271

APA

Puelles, V. G., van der Wolde, J. W., Wanner, N., Scheppach, M. W., Cullen-McEwen, L. A., Bork, T., Lindenmeyer, M. T., Gernhold, L., Wong, M. N., Braun, F., Cohen, C. D., Kett, M. M., Kuppe, C., Kramann, R., Saritas, T., van Roeyen, C. R., Moeller, M. J., Tribolet, L., Rebello, R., ... Bertram, J. F. (2019). mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI INSIGHT, 4(18). https://doi.org/10.1172/jci.insight.99271

Vancouver

Puelles VG, van der Wolde JW, Wanner N, Scheppach MW, Cullen-McEwen LA, Bork T et al. mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI INSIGHT. 2019 Sep 19;4(18). https://doi.org/10.1172/jci.insight.99271

Bibtex

@article{ee7747e754c147cab0078583f82e178e,
title = "mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans",
abstract = "The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.",
author = "Puelles, {Victor G} and {van der Wolde}, {James W} and Nicola Wanner and Scheppach, {Markus W} and Cullen-McEwen, {Luise A} and Tillmann Bork and Lindenmeyer, {Maja T} and Lukas Gernhold and Wong, {Milagros N} and Fabian Braun and Cohen, {Clemens D} and Kett, {Michelle M} and Christoph Kuppe and Rafael Kramann and Turgay Saritas and {van Roeyen}, {Claudia R} and Moeller, {Marcus J} and Leon Tribolet and Richard Rebello and Sun, {Yu By} and Jinhua Li and Gerard M{\"u}ller-Newen and Hughson, {Michael D} and Hoy, {Wendy E} and Fermin Person and Thorsten Wiech and Ricardo, {Sharon D} and Kerr, {Peter G} and Denton, {Kate M} and Luc Furic and Huber, {Tobias B} and Nikolic-Paterson, {David J} and Bertram, {John F}",
year = "2019",
month = sep,
day = "19",
doi = "10.1172/jci.insight.99271",
language = "English",
volume = "4",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "18",

}

RIS

TY - JOUR

T1 - mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

AU - Puelles, Victor G

AU - van der Wolde, James W

AU - Wanner, Nicola

AU - Scheppach, Markus W

AU - Cullen-McEwen, Luise A

AU - Bork, Tillmann

AU - Lindenmeyer, Maja T

AU - Gernhold, Lukas

AU - Wong, Milagros N

AU - Braun, Fabian

AU - Cohen, Clemens D

AU - Kett, Michelle M

AU - Kuppe, Christoph

AU - Kramann, Rafael

AU - Saritas, Turgay

AU - van Roeyen, Claudia R

AU - Moeller, Marcus J

AU - Tribolet, Leon

AU - Rebello, Richard

AU - Sun, Yu By

AU - Li, Jinhua

AU - Müller-Newen, Gerard

AU - Hughson, Michael D

AU - Hoy, Wendy E

AU - Person, Fermin

AU - Wiech, Thorsten

AU - Ricardo, Sharon D

AU - Kerr, Peter G

AU - Denton, Kate M

AU - Furic, Luc

AU - Huber, Tobias B

AU - Nikolic-Paterson, David J

AU - Bertram, John F

PY - 2019/9/19

Y1 - 2019/9/19

N2 - The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.

AB - The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.

U2 - 10.1172/jci.insight.99271

DO - 10.1172/jci.insight.99271

M3 - SCORING: Journal article

C2 - 31534053

VL - 4

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 18

ER -