Metabolic reprogramming and tolerance during sepsis-induced AKI

Abstract

The host defence against infection is an adaptive response in which several mechanisms are deployed to decrease the pathogen load, limit tissue injury and restore homeostasis. In the past few years new evidence has suggested that the ability of the immune system to limit the microbial burden — termed resistance — might not be the only defence mechanism. In fact, the capacity of the host to decrease its own susceptibility to inflammation- induced tissue damage — termed tolerance — might be as important as resistance in determining the outcome of the infection. Metabolic adaptations are central to the function of the cellular immune response. Coordinated reprogramming of metabolic signalling enables cells to execute resistance and tolerance pathways, withstand injury, steer tissue repair and promote organ recovery. During sepsis-induced acute kidney injury, early reprogramming of metabolism can determine the extent of organ dysfunction, progression to fibrosis, and the development of chronic kidney disease. Here we discuss the mechanisms of tolerance that act in the kidney during sepsis, with particular attention to the role of metabolic responses in coordinating these adaptive strategies. We suggest a novel conceptual model of the cellular and organic response to sepsis that might lead to new avenues for targeted, organ-protective therapies.

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…Once activated, these SIRTs play the dominant role in the development of a hypo-inflammatory state and an environment of metabolic downregulation and reductions in glycolysis and TCA-induced oxidative phosphorylation characterised by mitochondrial ATP production via fatty acid oxidation (Gómez et al 2017; Vachharajani et al 2016). This adaptive low-energy state is often described as cellular ‘hibernation’ (Levy et al 2005; Liu et al 2011a; Singer 2008) (reviewed (Singer 2017)) and it is important to stress that this phenomenon is not limited to macrophages and monocytes but also takes place in hepatocytes and striated muscle cells (Carré and Singer 2008; McCall et al 2011; Singer 2007, 2008).…”

Novel roles for mucin 1 in the kidney

“…The function of Muc1/MUC1 in kidney has been more difficult to address as direct infection by bacteria and virus is much less common. While sepsis does stress the kidney primarily by indirect means, the most well characterized model of acute kidney injury is produced by clamping both the renal artery and vein, or the artery alone, to produce ischemia, and studying recovery of kidney function and morphology after return of blood flow for hours to days [28-30]. Using this approach, we found that Muc1 is protective in the kidney in a mouse model of ischemia-reperfusion injury by transactivation of the HIF-1 and β-catenin protective pathways [31,32].…”

How Does Continuous Renal Replacement Therapy Affect Septic Acute Kidney Injury?

“…This has been considered a result of metabolic adaptation [37]. Metabolic adaptation is like a protective response to inflammation.…”

“…Metabolic adaptation is like a protective response to inflammation. It increases the circulating levels of glucose by stimulating glycogenolysis and gluconeogenesis [38] and switches metabolism from regulatory energy pathways toward aerobic glycolysis, similar to the Warburg effect in cancer cells [37]. The elevated glucose enables the elevation of aerobic glycolysis in immune cells, which provide metabolic intermediates necessary for the expansion of biomass in immune cells and promotion of tissue repair [39].…”