Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis
| Autor: | Jitske Jansen, Marinka Bakker-van Bebber, Fieke Mooren, Markus A. Loeven, Brigith Willemsen, Jennifer Eymael, Catherine Meyer-Schwesinger, Bart Smeets, Shagun Sharma, Jack F.M. Wetzels, Henry B.P.M. Dijkman, Johan van der Vlag, Laura Miesen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pathology 030232 urology & nephrology lcsh:Medicine urologic and male genital diseases Podocyte Mice 0302 clinical medicine Focal segmental glomerulosclerosis lcsh:Science Multidisciplinary Glomerulosclerosis Focal Segmental TOR Serine-Threonine Kinases Hyperplasia female genital diseases and pregnancy complications medicine.anatomical_structure Drug therapy medicine.symptom Immunosuppressive Agents Signal Transduction medicine.drug medicine.medical_specialty Mice Transgenic Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] Article 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center medicine Albuminuria Animals Humans PI3K/AKT/mTOR pathway Cell Proliferation Sirolimus Sclerosis business.industry urogenital system lcsh:R Glomerulosclerosis medicine.disease Mice Inbred C57BL 030104 developmental biology Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] Thy-1 Antigens lcsh:Q Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] business Immunostaining |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Scientific Reports, 10 Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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