Reprogramming Metabolism to Enhance Kidney Tolerance during Sepsis: The Role of Fatty Acid Oxidation, Aerobic Glycolysis, and Epithelial De-Differentiation

Abstract

<b><i>Background:</i></b> The recognition that sepsis induces acute kidney injury (AKI) in the absence of overt necrosis or apoptosis and even in the presence of increased renal blood flow has led to the consideration that kidney tubular epithelial cells (TECs) may deploy defense mechanisms to survive the insult. <b><i>Summary:</i></b> This concept dovetails well with the notion that the defense against infection not only depends on the capacity of the immune system to limit the microbial burden or resistance capacity but also on the capacity of the host to limit tissue injury, collectively known as tolerance. To sustain the high energy requirement that ion transport mandates, kidney TECs use fatty acid oxidation (FAO) as one of the preferred sources of energy. Inflammatory processes like endotoxemia and sepsis decrease mitochondrial FAO and hinder mitochondrial respiration. Impaired FAO is associated with TEC de-differentiation, loss of kidney function, and TEC injury through lipotoxicity and oxidative stress in the acute setting, and with maladaptive repair and fibrosis after AKI in the latter stages. AMP-activated protein kinase (AMPK) is a master regulator of energy and promoter of FAO that can be activated pharmacologically to protect against AKI and death during experimental sepsis, operating through a tolerance mechanism. <b><i>Key Messages:</i></b> Organ dysfunction during sepsis is the expression of tissue injury and adaptive defense mechanisms operating through resistance or tolerance that prioritize cell survival over organ function. Metabolic reprogramming away from FAO/oxidative phosphorylation seems to be a common pathological denominator throughout the AKI continuum that may be targeted through the activation of AMPK.