Metabolic Reprogramming and Host Tolerance: A Novel Concept to Understand Sepsis-Associated AKI

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.

Keywords: AKI; metabolism; mitochondria; sepsis; tolerance.

Figure 1

Reaction norm demonstrating the concept of Tolerance and Resistance. (A) Host fitness is plotted against bacterial burden for two different hosts (Host A, solid line, and Host B, dashed line). As the figure shows, for the same bacterial burden (same mean pathogen load in x-axis), the health cost (i.e., the change in Host fitness) of such infection is greater for host A than for host B. The slope of the curves is representative therefore, of the Tolerance capacity of each host. (B) Host fitness is plotted against bacterial burden once again for two different hosts (Host C, solid line, and Host D, dashed line). Host C and D have the same Tolerance capacity because the slopes of the curves are identical. However, Host D has lower Resistance capacity than Host C because the mean pathogen load is higher.

Figure 2

Hypothetical scheme of the regulatory nodes driving metabolic reprogramming toward aerobic glycolysis (left panel) or oxidative phosphorylation (right panel) in the kidney tubular epithelial cell. During early inflammation, activation of HIF-1α through the Akt/mTORC1 pathway, results in the expression of PKM2 and PDHK, which inhibits the conversion of pyruvate into Acetyl CoA, and therefore its entry into the mitochondria. This early phase is followed by a late phase, where the cell returns to the default metabolic phenotype which relies on OXPHOS for energy production. This switch is led by the cooperative activation of AMPK, PGC-1α, Sirt 1 and Sirt 6. AMPK, PGC-1α and Sirt 1 are the key regulatory nodes that promote fatty acid oxidation and glucose oxidation (i.e., OXPHOS), whereas Sirt 6 may have a role in inhibiting the actions of HIF-1α on glycolytic enzyme expression. ACC, acetyl co-enzyme A carboxylase; AMP, adenosine monophosphate; ATP, adenosine triphosphate; MCP-1, monocyte chemoattractant molecule 1; NAD+, nicotinamide adenine dinucleotide (oxidized); NADH, nicotinamide adenine dinucleotide (reduced); TH17, type 17 T helper; TNF, tumor necrosis factor; Treg, regulatory T cell. Modified from ( [40] and Pool R; Gomez H; Kellum J.A; Mechanisms of Organ Dysfunction in Sepsis. Crit Care Clin. 2018 Jan, 34(1), 63–80).

Figure 3

C57/BL6 mice were exposed to either sham surgery (Sham) or cecal ligation and puncture (CLP), and were treated with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), (CLP+A) or vehicle (CLP). At 24 h, the animals were sacrificed and samples were obtained to assess outcomes. For more details on the experimental design please see the Supplementary Material. There was no difference in the bacterial colony forming units (CFU) between mice treated with AICAR or vehicle in the peritoneal fluid (A) or in blood (B). In addition, there were no differences in plasma levels of interleukin-6 (IL-6) (C). These results suggest that protection through AMPK activation is independent of resistance because there was no effect on bacterial burden, and therefore, must be operating through a Tolerance mechanism. * p value < 0.05 when compared to sham.