Abstract
Acute kidney injury (AKI) is a frequent complication of sepsis that increases mortality and the risk of progression to chronic kidney disease. However, the mechanisms leading to sepsis-associated AKI are still poorly understood. The recognition that sepsis induces organ dysfunction in the absence of overt necrosis or apoptosis has led to the consideration that tubular epithelial cells (TEC) may deploy defense mechanisms to survive the insult. This concept dovetails well with the notion that the defense against infection does not only depend on the capacity of the immune system to limit the microbial load (known as resistance), but also on the capacity of cells and tissues to limit tissue injury (known as tolerance). In this review, we discuss the importance of TEC metabolic reprogramming as a defense strategy during sepsis, and how this cellular response is likely to operate through a tolerance mechanism. We discuss the fundamental role of specific regulatory nodes and of mitochondria in orchestrating this response, and how this opens avenues for the exploration of targeted therapeutic strategies to prevent or treat sepsis-associated AKI.
Highlights
Sepsis is a common and life-threatening condition defined as a dysregulated immune response to infection associated with severe organ dysfunction [1]
Using gas chromatography/mass spectrometry analysis of kidney biopsies obtained 8 h after the induction of sepsis by cecal-ligation and puncture (CLP), we have shown an increase in glycolytic intermediates and a decrease in intermediates of the tricarboxylic acid cycle (TCA) suggestive of a switch in kidney metabolic phenotype toward glycolysis [50]
With the above in mind, we have recently shown that pharmacologic activation of AMPK, using 5-aminoimidazole-4-carboxamide ribunocleotide (AICAR) or metformin, protects against the development of acute kidney injury (AKI) and increases survival in rodent models of CLPinduced sepsis [64,89]
Summary
Sepsis is a common and life-threatening condition defined as a dysregulated immune response to infection associated with severe organ dysfunction [1]. Sepsis-associated acute kidney injury (AKI) occurs in more than 50% of patients with septic shock [4], which increases the risk of death by 30–50% [5,6]. Demonstrated that hypoperfusion is not necessary for the development of organ dysfunction, because AKI still occurred in the absence of decreased renal blood flow. These disruptive findings have led to the consideration that cells are successful at defending from inflammatory injury and avoiding death, and to the hypothesis that early organ dysfunction may be the representation of such success.
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