Abstract
Septic acute kidney injury (AKI) associates with poor survival rates and often requires renal replacement therapy. Glucocorticoids may pose renal protective effects in sepsis via stimulation of mitochondrial function. Therefore, we studied the mitochondrial effects of dexamethasone in an experimental inflammatory proximal tubule epithelial cell model. Treatment of human proximal tubule epithelial cells with lipopolysaccharide (LPS) closely resembles pathophysiological processes during endotoxaemia, and led to increased cytokine excretion rates and cellular reactive oxygen species levels, combined with a reduced mitochondrial membrane potential and respiratory capacity. These effects were attenuated by dexamethasone. Dexamethasone specifically increased the expression and activity of mitochondrial complex V (CV), which could not be explained by an increase in mitochondrial mass. Finally, we demonstrated that dexamethasone acidified the intracellular milieu and consequently reversed LPS-induced alkalisation, leading to restoration of the mitochondrial function. This acidification also provides an explanation for the increase in CV expression, which is expected to compensate for the inhibitory effect of the acidified environment on this complex. Besides the mechanistic insights into the beneficial effects of dexamethasone during renal cellular inflammation, our work also supports a key role for mitochondria in this process and, hence, provides novel therapeutic avenues for the treatment of AKI.
Highlights
The prevalence of acute kidney injury (AKI) in critically ill patients has rapidly increased over the past two decades up to 30 to 40% of patients admitted to the intensive care unit[1, 2]
complex IV (CIV)-driven respiration was not reduced after LPS treatment, which could be explained by the auto-oxidative potential of the substrates used (i.e. ascorbate and N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)) leading to a decreased sensitivity (Fig. 3c)
Respiratory inhibition by LPS was only apparent upon maximal stimulation of the respiratory chain in permeabilised cells, as observed for the respiration driven by CI (32 ± 13%, p = 0.00041), complex II (CII) (27 ± 13%, p = 0.000061), and glycerol-3-phosphate dehydrogenase (G3PDH; 34 ± 16%, p = 0.0087) respiration, but not under basal conditions (Fig. 3b,c)
Summary
The prevalence of acute kidney injury (AKI) in critically ill patients has rapidly increased over the past two decades up to 30 to 40% of patients admitted to the intensive care unit[1, 2]. Protective mechanisms have been explored in vitro for their therapeutic potency in AKI (e.g. antioxidant, anti-inflammatory, or anti-apoptotic effects, or the activation of autophagy)[6]. Still, most of these strategies have not yet reached clinical studies, and none are applied in a clinical setting[7]. Further clinical validation should demonstrate the true efficacy and efficiency of AP prior to clinical implementation Another potential replacement therapy includes a bioartificial kidney containing renal proximal tubule epithelial cells to correct uraemia. Further elucidation of the exact mechanism by which dexamethasone influences mitochondrial homeostasis pathways during AKI is required
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