Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

Abstract

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10-to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O 2 consumption rates (OCR) and the membrane potential (Δψ m ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects | 7037 JIN et al.

Inhibition of aerobic glycolysis alleviates sepsis‑induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK‑regulated autophagy

“…Modulation of sepsis-enhanced glycolysis with 2-DG improved the survival outcome by decreasing MKK3 phosphorylation and increasing SIRT3 expression (18). Moreover, Jin et al recently revealed that renal AMPK activation protected from sepsis-induced AKI by preserving mitochondrial function and metabolic fitness likely through SIRT3 signaling (39). The aforementioned results are consistent with the results of the present study.…”

Dexmedetomidine Enhances Autophagy via α2-AR/AMPK/mTOR Pathway to Inhibit the Activation of NLRP3 Inflammasome and Subsequently Alleviates Lipopolysaccharide-Induced Acute Kidney Injury

“…AKI induced by sepsis is closely associated with excessive inflammatory responses and severe renal impairment. Indeed, the kidney is one of the earliest and most frequently affected organs during sepsis ( Bagshaw et al, 2008 ; Jin et al, 2020 ). Therefore, early intervention can prevent further exacerbation of AKI and more serious damage caused by sepsis.…”

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

“…We have shown that pharmacologic activation of AMPK, a master regulator of energy, promoter of OXPHOS, and inhibitor of Warburg metabolism [ 63 ], improves survival in rodents exposed to CLP. More importantly, we have demonstrated that AMPK activation decreases the development of AKI, suggesting that the survival advantage may be associated with reducing organ dysfunction [ 64 ].…”

“…Furthermore, they demonstrated that stimulation of PGC-1α improves the survival of rodents exposed to ischemia reperfusion injury [ 69 ] and following LPS [ 51 ], suggesting that the stimulation of regulators of FAO and OXPHOS improves outcome and that a shift toward OXPHOS may follow a similar blueprint as in inflammatory cells. Activation of PGC-1α requires a coordinated sequence of phosphorylation and deacetylation by AMPK and Sirtuin 1, respectively [ 64 , 67 ]. AMPK indirectly can also activate Sirtuin 1 by increasing nicotinamide adenine dinucleotide (NAD + ) availability.…”

“…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 AKI and increases survival in rodent models of CLP-induced sepsis [ 64 , 89 ]. However, it remains unclear how AMPK activation provides protective effects.…”