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Scavengers of reactive oxygen species, paracalcitol, RhoA and Rac-1 inhibitors and tacrolimus inhibit angiotensin II induced actions on glomerular permeability.

Axelsson, Josefin LU ; Rippe, Anna LU ; Sverrisson, Kristinn LU and Rippe, Bengt LU (2013) In American Journal of Physiology-Renal Physiology 305(3). p.237-243
Abstract
Systemic infusions of angiotensin II (AngII) rapidly induce large, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), AngII generates reactive oxygen species (ROS) and produces Ca(2+) influx into cells, leading to activation of a plethora of signaling cascades, including e.g. calcineurin, and small GTPases, such as Rac-1 and RhoA. In the present study we sought to interact with some of these cascades in order to test potential novel antiproteinuric agents. In anaesthetized Wistar rats the left urether was cannulated for urine collection, and blood access was achieved. Rats were infused with AngII (16 ng/kg/min) alone, or together with the ROS scavengers, TEMPOL or... (More)
Systemic infusions of angiotensin II (AngII) rapidly induce large, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), AngII generates reactive oxygen species (ROS) and produces Ca(2+) influx into cells, leading to activation of a plethora of signaling cascades, including e.g. calcineurin, and small GTPases, such as Rac-1 and RhoA. In the present study we sought to interact with some of these cascades in order to test potential novel antiproteinuric agents. In anaesthetized Wistar rats the left urether was cannulated for urine collection, and blood access was achieved. Rats were infused with AngII (16 ng/kg/min) alone, or together with the ROS scavengers, TEMPOL or dimethylthiourea (DMTU), or the D-vitamin analog, paracalcitol, the RhoA-kinase inhibitor, Y-27632, the Rac-1 inhibitor, NSC-23766, or the calcineurin inhibitor, tacrolimus. FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA were infused throughout the experiment. Plasma and urine samples were taken during baseline and at 5 and 15 min after the start of the infusions and analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ) for Ficoll10-80Å. AngII infusion into rats caused marked increases in glomerular permeability to large Ficoll molecules (Ficoll50-80Å), which were abrogated by the ROS scavenger TEMPOL and partly by DMTU. Paracalcitol, RhoA and Rac-1 inhibition, and, to some extent, tacrolimus, but not prostacyclin, could also inhibit the glomerular permeability actions of AngII. Our data suggest that cellular ROS generation and active Ca(2+) signaling are involved in AngII induced increases in glomerular permeability. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Physiology-Renal Physiology
volume
305
issue
3
pages
237 - 243
publisher
American Physiological Society
external identifiers
  • wos:000322699000003
  • pmid:23657856
  • scopus:84881013153
ISSN
1522-1466
DOI
10.1152/ajprenal.00154.2013
language
English
LU publication?
yes
id
ec03b513-2657-4b54-bac5-c0cee3accec1 (old id 3804733)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23657856?dopt=Abstract
date added to LUP
2013-06-06 16:02:27
date last changed
2019-07-16 01:19:28
@article{ec03b513-2657-4b54-bac5-c0cee3accec1,
  abstract     = {Systemic infusions of angiotensin II (AngII) rapidly induce large, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), AngII generates reactive oxygen species (ROS) and produces Ca(2+) influx into cells, leading to activation of a plethora of signaling cascades, including e.g. calcineurin, and small GTPases, such as Rac-1 and RhoA. In the present study we sought to interact with some of these cascades in order to test potential novel antiproteinuric agents. In anaesthetized Wistar rats the left urether was cannulated for urine collection, and blood access was achieved. Rats were infused with AngII (16 ng/kg/min) alone, or together with the ROS scavengers, TEMPOL or dimethylthiourea (DMTU), or the D-vitamin analog, paracalcitol, the RhoA-kinase inhibitor, Y-27632, the Rac-1 inhibitor, NSC-23766, or the calcineurin inhibitor, tacrolimus. FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA were infused throughout the experiment. Plasma and urine samples were taken during baseline and at 5 and 15 min after the start of the infusions and analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ) for Ficoll10-80Å. AngII infusion into rats caused marked increases in glomerular permeability to large Ficoll molecules (Ficoll50-80Å), which were abrogated by the ROS scavenger TEMPOL and partly by DMTU. Paracalcitol, RhoA and Rac-1 inhibition, and, to some extent, tacrolimus, but not prostacyclin, could also inhibit the glomerular permeability actions of AngII. Our data suggest that cellular ROS generation and active Ca(2+) signaling are involved in AngII induced increases in glomerular permeability.},
  author       = {Axelsson, Josefin and Rippe, Anna and Sverrisson, Kristinn and Rippe, Bengt},
  issn         = {1522-1466},
  language     = {eng},
  number       = {3},
  pages        = {237--243},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology-Renal Physiology},
  title        = {Scavengers of reactive oxygen species, paracalcitol, RhoA and Rac-1 inhibitors and tacrolimus inhibit angiotensin II induced actions on glomerular permeability.},
  url          = {http://dx.doi.org/10.1152/ajprenal.00154.2013},
  volume       = {305},
  year         = {2013},
}