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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTORmediated) 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.

Original languageEnglish
Article numbere99271
Number of pages18
JournalJCI Insight
Volume4
Issue number18
DOIs
Publication statusPublished - 19 Sep 2019

Cite this

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 B.Y. ; 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. / MTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. In: JCI Insight. 2019 ; Vol. 4, No. 18.
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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 (mTORmediated) 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 B.Y.} 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 = "9",
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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, YBY, 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, vol. 4, no. 18, e99271. https://doi.org/10.1172/jci.insight.99271

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 B.Y.; 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, Vol. 4, No. 18, e99271, 19.09.2019.

Research output: Contribution to journalArticleResearchpeer-review

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 B.Y.

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 (mTORmediated) 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 (mTORmediated) 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.

UR - http://www.scopus.com/inward/record.url?scp=85072671990&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.99271

DO - 10.1172/jci.insight.99271

M3 - Article

C2 - 31534053

AN - SCOPUS:85072671990

VL - 4

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 18

M1 - e99271

ER -