Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury.
Acute Kidney Injury
/ drug therapy
Animals
Antihypertensive Agents
/ pharmacology
Biomarkers
/ metabolism
Blood Urea Nitrogen
Caspase 3
/ metabolism
Creatinine
/ blood
Disease Models, Animal
Epoprostenol
/ analogs & derivatives
Interleukin-1beta
/ metabolism
Kidney Function Tests
Lipocalin-2
/ metabolism
Male
Rats
Rats, Sprague-Dawley
Reperfusion Injury
/ complications
acute kidney injury
apoptosis
ischemia–reperfusion injury
oxidative stress
prostacyclin
Journal
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
ISSN: 1460-2385
Titre abrégé: Nephrol Dial Transplant
Pays: England
ID NLM: 8706402
Informations de publication
Date de publication:
25 01 2021
25 01 2021
Historique:
received:
06
01
2020
pubmed:
7
11
2020
medline:
11
5
2021
entrez:
6
11
2020
Statut:
ppublish
Résumé
Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo. Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia. Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil. This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.
Sections du résumé
BACKGROUND
Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo.
METHODS
Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.
RESULTS
Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.
CONCLUSIONS
This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.
Identifiants
pubmed: 33156922
pii: 5959832
doi: 10.1093/ndt/gfaa236
pmc: PMC7834597
doi:
Substances chimiques
Antihypertensive Agents
0
Biomarkers
0
IL1B protein, human
0
Interleukin-1beta
0
LCN2 protein, human
0
Lcn2 protein, rat
0
Lipocalin-2
0
Creatinine
AYI8EX34EU
Epoprostenol
DCR9Z582X0
CASP3 protein, human
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
treprostinil
RUM6K67ESG
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
257-266Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103430
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM115677
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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