Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Cystathionine-γ-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis
Ist Teil von
Intensive care medicine experimental, 2018-10, Vol.6 (1), p.43-14, Article 43
Ort / Verlag
Cham: Springer International Publishing
Erscheinungsjahr
2018
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Background
Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H
2
S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease.
Methods
This study is a
post hoc
analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood
13
C
6
-glucose and expiratory
13
CO
2
/
12
CO
2
isotope enrichment during
13
C
6
-glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections.
Results
Sepsis was associated with lactic acidosis (
p
= 0.004) and AKI (50% fall of creatinine clearance (CrCl),
p
= 0.019). While both whole-body glucose production (
p
= 0.004) and oxidation (
p
= 0.006) were increased, kidney tissue mitochondrial respiration was reduced (
p
= 0.028), coinciding with decreased CSE (
p
= 0.003) and PGC1α (
p
= 0.003) expression. Albumin extravasation (
p
= 0.011) and nitrotyrosine formation (
p
= 0.008) were increased in septic kidneys.
Conclusions
Sepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.