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Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis

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Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis. / Miesen, Laura; Eymael, Jennifer; Sharma, Shagun; Loeven, Markus A; Willemsen, Brigith; Bakker-van Bebber, Marinka; Mooren, Fieke; Meyer-Schwesinger, Catherine; Dijkman, Henry; Wetzels, Jack F M; Jansen, Jitske; van der Vlag, Johan; Smeets, Bart.

In: SCI REP-UK, Vol. 10, No. 1, 22.05.2020, p. 8580.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Miesen, L, Eymael, J, Sharma, S, Loeven, MA, Willemsen, B, Bakker-van Bebber, M, Mooren, F, Meyer-Schwesinger, C, Dijkman, H, Wetzels, JFM, Jansen, J, van der Vlag, J & Smeets, B 2020, 'Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis', SCI REP-UK, vol. 10, no. 1, pp. 8580. https://doi.org/10.1038/s41598-020-65352-y

APA

Miesen, L., Eymael, J., Sharma, S., Loeven, M. A., Willemsen, B., Bakker-van Bebber, M., Mooren, F., Meyer-Schwesinger, C., Dijkman, H., Wetzels, J. F. M., Jansen, J., van der Vlag, J., & Smeets, B. (2020). Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis. SCI REP-UK, 10(1), 8580. https://doi.org/10.1038/s41598-020-65352-y

Vancouver

Miesen L, Eymael J, Sharma S, Loeven MA, Willemsen B, Bakker-van Bebber M et al. Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis. SCI REP-UK. 2020 May 22;10(1):8580. https://doi.org/10.1038/s41598-020-65352-y

Bibtex

@article{a15c05811832476bb0601fb1ec35ddc1,
title = "Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis",
abstract = "Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.",
keywords = "Albuminuria/drug therapy, Animals, Cell Proliferation, Glomerulosclerosis, Focal Segmental/drug therapy, Humans, Immunosuppressive Agents/pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Sclerosis/drug therapy, Signal Transduction, Sirolimus/pharmacology, TOR Serine-Threonine Kinases/antagonists & inhibitors, Thy-1 Antigens/physiology",
author = "Laura Miesen and Jennifer Eymael and Shagun Sharma and Loeven, {Markus A} and Brigith Willemsen and {Bakker-van Bebber}, Marinka and Fieke Mooren and Catherine Meyer-Schwesinger and Henry Dijkman and Wetzels, {Jack F M} and Jitske Jansen and {van der Vlag}, Johan and Bart Smeets",
year = "2020",
month = may,
day = "22",
doi = "10.1038/s41598-020-65352-y",
language = "English",
volume = "10",
pages = "8580",
journal = "SCI REP-UK",
issn = "2045-2322",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis

AU - Miesen, Laura

AU - Eymael, Jennifer

AU - Sharma, Shagun

AU - Loeven, Markus A

AU - Willemsen, Brigith

AU - Bakker-van Bebber, Marinka

AU - Mooren, Fieke

AU - Meyer-Schwesinger, Catherine

AU - Dijkman, Henry

AU - Wetzels, Jack F M

AU - Jansen, Jitske

AU - van der Vlag, Johan

AU - Smeets, Bart

PY - 2020/5/22

Y1 - 2020/5/22

N2 - Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.

AB - Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.

KW - Albuminuria/drug therapy

KW - Animals

KW - Cell Proliferation

KW - Glomerulosclerosis, Focal Segmental/drug therapy

KW - Humans

KW - Immunosuppressive Agents/pharmacology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Sclerosis/drug therapy

KW - Signal Transduction

KW - Sirolimus/pharmacology

KW - TOR Serine-Threonine Kinases/antagonists & inhibitors

KW - Thy-1 Antigens/physiology

U2 - 10.1038/s41598-020-65352-y

DO - 10.1038/s41598-020-65352-y

M3 - SCORING: Journal article

C2 - 32444668

VL - 10

SP - 8580

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -