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mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside.

Axelsson, Josefin LU ; Rippe, Anna LU and Rippe, Bengt LU (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)
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Contribution to journal
publication status
published
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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
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
2015-04-02 14:27:45
date last changed
2017-07-23 03:14:48
@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},
  volume       = {308},
  year         = {2015},
}