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Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETa receptor

Dolinina, Julia LU ; Rippe, Anna LU and Öberg, Carl M. LU (2019) In American Journal of Physiology - Renal Physiology 316(6). p.1173-1179
Abstract

Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETA receptor. Am J Physiol Renal Physiol 316: F1173–F1179, 2019. First published March 13, 2019; doi:10.1152/ajprenal.00040.2019.—Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients... (More)

Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETA receptor. Am J Physiol Renal Physiol 316: F1173–F1179, 2019. First published March 13, 2019; doi:10.1152/ajprenal.00040.2019.—Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients for neutral FITC-Ficoll (molecular Stokes-Einstein radius: 15–80 Å, molecular weight: 70 kDa/400 kDa) in anesthetized male Sprague-Dawley rats (n = 12) at baseline and at 5, 15, 30, and 60 min after intravenous administration of ET-1. In separate experiments, ET-1 was given together with the selective ET type A (ETA) or ET type B (ETB) receptor antagonists JKC-301 and BQ-788, respectively. At both 15 and 30 min postadministration, the glomerular sieving coefficient for macromolecular Ficoll (70 Å) was significantly increased to 4.4 x 10-5  0.7 x 10-5 (P = 0.024) and 4.5 x 10-5  0.8 x 10-5 (P = 0.007), respectively, compared with baseline (2.2 x 10-5  0.4 x10-5). Decreased urine production after ET-1 prevented the use of higher doses of ET-1. Data analysis using the two-pore model indicated changes in large-pore permeability after ET-1, with no changes in the small-pore pathway. Administration of ETA blocker abrogated the permeability changes induced by ET-1 at 30 min, whereas blockade of ETB receptors was ineffective. Mean arterial pressure was only significantly increased at 60 min, being 123  4 mmHg compared with 111  2 mmHg at baseline (P = 0.02). We conclude that ET-1 evoked small, delayed, and sustained increases in glomerular permeability, mediated via the ETA receptor.

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published
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in
American Journal of Physiology - Renal Physiology
volume
316
issue
6
pages
1173 - 1179
publisher
American Physiological Society
external identifiers
  • scopus:85067097627
ISSN
0363-6127
DOI
10.1152/ajprenal.00040.2019
language
English
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yes
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7b9a9085-3de5-49bd-b026-9ff2bde02248
date added to LUP
2019-07-01 13:16:40
date last changed
2019-07-16 04:13:44
@article{7b9a9085-3de5-49bd-b026-9ff2bde02248,
  abstract     = {<p>Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ET<sub>A</sub> receptor. Am J Physiol Renal Physiol 316: F1173–F1179, 2019. First published March 13, 2019; doi:10.1152/ajprenal.00040.2019.—Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients for neutral FITC-Ficoll (molecular Stokes-Einstein radius: 15–80 Å, molecular weight: 70 kDa/400 kDa) in anesthetized male Sprague-Dawley rats (n = 12) at baseline and at 5, 15, 30, and 60 min after intravenous administration of ET-1. In separate experiments, ET-1 was given together with the selective ET type A (ET<sub>A</sub>) or ET type B (ET<sub>B</sub>) receptor antagonists JKC-301 and BQ-788, respectively. At both 15 and 30 min postadministration, the glomerular sieving coefficient for macromolecular Ficoll (70 Å) was significantly increased to 4.4 x 10<sup>-5</sup>  0.7 x 10<sup>-5</sup> (P = 0.024) and 4.5 x 10<sup>-5</sup>  0.8 x 10<sup>-5</sup> (P = 0.007), respectively, compared with baseline (2.2 x 10<sup>-5</sup>  0.4 x10<sup>-5</sup>). Decreased urine production after ET-1 prevented the use of higher doses of ET-1. Data analysis using the two-pore model indicated changes in large-pore permeability after ET-1, with no changes in the small-pore pathway. Administration of ET<sub>A</sub> blocker abrogated the permeability changes induced by ET-1 at 30 min, whereas blockade of ET<sub>B</sub> receptors was ineffective. Mean arterial pressure was only significantly increased at 60 min, being 123  4 mmHg compared with 111  2 mmHg at baseline (P = 0.02). We conclude that ET-1 evoked small, delayed, and sustained increases in glomerular permeability, mediated via the ET<sub>A</sub> receptor.</p>},
  author       = {Dolinina, Julia and Rippe, Anna and Öberg, Carl M.},
  issn         = {0363-6127},
  language     = {eng},
  number       = {6},
  pages        = {1173--1179},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology - Renal Physiology},
  title        = {Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ET<sub>a</sub> receptor},
  url          = {http://dx.doi.org/10.1152/ajprenal.00040.2019},
  volume       = {316},
  year         = {2019},
}