Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model.
<h4>Background</h4>The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, di...
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oai:doaj.org-article:af232cd236874a11ba395d91515663ac2021-11-18T07:25:33ZDelayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model.1932-620310.1371/journal.pone.0032516https://doaj.org/article/af232cd236874a11ba395d91515663ac2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22427849/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats.<h4>Methods</h4>This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation.<h4>Results</h4>Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model.<h4>Conclusion</h4>Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.Melania KurdiánInmaculada Herrero-FresnedaNuria LloberasPepita Gimenez-BonafeVirginia CoriaMaría T GrandeJosé BoggiaLeonel MalacridaJoan TorrasMiguel A ArévaloFrancisco González-MartínezJosé M López-NovoaJosep GrinyóOscar NoboaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e32516 (2012) |
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Medicine R Science Q Melania Kurdián Inmaculada Herrero-Fresneda Nuria Lloberas Pepita Gimenez-Bonafe Virginia Coria María T Grande José Boggia Leonel Malacrida Joan Torras Miguel A Arévalo Francisco González-Martínez José M López-Novoa Josep Grinyó Oscar Noboa Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| description |
<h4>Background</h4>The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats.<h4>Methods</h4>This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation.<h4>Results</h4>Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model.<h4>Conclusion</h4>Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin. |
| format |
article |
| author |
Melania Kurdián Inmaculada Herrero-Fresneda Nuria Lloberas Pepita Gimenez-Bonafe Virginia Coria María T Grande José Boggia Leonel Malacrida Joan Torras Miguel A Arévalo Francisco González-Martínez José M López-Novoa Josep Grinyó Oscar Noboa |
| author_facet |
Melania Kurdián Inmaculada Herrero-Fresneda Nuria Lloberas Pepita Gimenez-Bonafe Virginia Coria María T Grande José Boggia Leonel Malacrida Joan Torras Miguel A Arévalo Francisco González-Martínez José M López-Novoa Josep Grinyó Oscar Noboa |
| author_sort |
Melania Kurdián |
| title |
Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| title_short |
Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| title_full |
Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| title_fullStr |
Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| title_full_unstemmed |
Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| title_sort |
delayed mtor inhibition with low dose of everolimus reduces tgfβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/af232cd236874a11ba395d91515663ac |
| work_keys_str_mv |
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