mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside.
(2015) In American Journal of Physiology-Renal Physiology 308(10). p.1056-1064- Abstract
- Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study we investigated whether glomerular permeability can be acutely altered by the mTORi, temsirolimus, and whether mTORi can affect acute purumycin aminonucleoside (PAN) or angiotensin II (AngII) induced glomerular hyperpermeability. In anaesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously, blood access was achieved. Temsirolimus was administered as a single dose i.v. 30 min before the start of the experiments in animals infused with PAN or AngII... (More)
- Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study we investigated whether glomerular permeability can be acutely altered by the mTORi, temsirolimus, and whether mTORi can affect acute purumycin aminonucleoside (PAN) or angiotensin II (AngII) induced glomerular hyperpermeability. In anaesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously, blood access was achieved. Temsirolimus was administered as a single dose i.v. 30 min before the start of the experiments in animals infused with PAN or AngII or in non-exposed animals. Polydispersed FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60 and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high performance size exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (θ) for Ficoll10-80Å. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80Å 45 min after its administration, a ROS dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger, tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate AngII or PAN induced increases in glomerular permeability. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5265260
- author
- Axelsson, Josefin LU ; Rippe, Anna LU and Rippe, Bengt LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- American Journal of Physiology-Renal Physiology
- volume
- 308
- issue
- 10
- pages
- 1056 - 1064
- publisher
- American Physiological Society
- external identifiers
-
- pmid:25740597
- wos:000354713000003
- scopus:84930833184
- pmid:25740597
- ISSN
- 1522-1466
- DOI
- 10.1152/ajprenal.00632.2014
- language
- English
- LU publication?
- yes
- id
- 76648c7e-2e4b-48de-a364-a92745ad3d9e (old id 5265260)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25740597?dopt=Abstract
- date added to LUP
- 2016-04-01 10:23:43
- date last changed
- 2022-01-25 22:46:53
@article{76648c7e-2e4b-48de-a364-a92745ad3d9e,
abstract = {{Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study we investigated whether glomerular permeability can be acutely altered by the mTORi, temsirolimus, and whether mTORi can affect acute purumycin aminonucleoside (PAN) or angiotensin II (AngII) induced glomerular hyperpermeability. In anaesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously, blood access was achieved. Temsirolimus was administered as a single dose i.v. 30 min before the start of the experiments in animals infused with PAN or AngII or in non-exposed animals. Polydispersed FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60 and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high performance size exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (θ) for Ficoll10-80Å. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80Å 45 min after its administration, a ROS dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger, tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate AngII or PAN induced increases in glomerular permeability.}},
author = {{Axelsson, Josefin and Rippe, Anna and Rippe, Bengt}},
issn = {{1522-1466}},
language = {{eng}},
number = {{10}},
pages = {{1056--1064}},
publisher = {{American Physiological Society}},
series = {{American Journal of Physiology-Renal Physiology}},
title = {{mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside.}},
url = {{http://dx.doi.org/10.1152/ajprenal.00632.2014}},
doi = {{10.1152/ajprenal.00632.2014}},
volume = {{308}},
year = {{2015}},
}