Abstract
BackgroundSepsis 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 H2S 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.MethodsThis 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 13C6-glucose and expiratory 13CO2/12CO2 isotope enrichment during 13C6-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.ResultsSepsis 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.ConclusionsSepsis-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.
Highlights
Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, leading to multiple organ dysfunction, e.g., acute kidney injury (AKI)
Sepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress
We recently demonstrated that CSE expression correlated with maintained creatinine clearance (CrCl) and reduced vascular leakage in resuscitated murine polymicrobial septic shock [1]
Summary
Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H2S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. CSE has been shown to play a role in regulating glucose metabolism and mitochondrial function through a PGC1α-dependent mechanism [8, 12]. We recently demonstrated the inverse relationship, suggesting a regulatory loop; in hyperglycemic septic mice, CSE protein expression was downregulated concomitant with reduced PGC1α levels and mitochondrial respiratory activity in both coupled (maximum oxidative phosphorylation (OxPhos)) and uncoupled (maximum capacity of the electron transfer system) states [8]. Its role in sepsis is ambivalent: In rodent endotoxemia or sepsis, H2S was reported to attenuate [15, 16] or aggravate [17] kidney dysfunction and/or injury
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