Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury

Abstract

Smith JA, Stallons LJ, Schnellmann RG. Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/ Akt signaling pathway in endotoxin-induced acute kidney injury. Am J Physiol Renal Physiol 307: F435-F444, 2014. First published July 2, 2014; doi:10.1152/ajprenal.00271.2014.-While disruption of energy production is an important contributor to renal injury, metabolic alterations in sepsis-induced AKI remain understudied. We assessed changes in renal cortical glycolytic metabolism in a mouse model of sepsis-induced AKI. A specific and rapid increase in hexokinase (HK) activity (ϳ2-fold) was observed 3 h after LPS exposure and maintained up to 18 h, in association with a decline in renal function as measured by blood urea nitrogen (BUN). LPS-induced HK activation occurred independently of HK isoform expression or mitochondrial localization. No other changes in glycolytic enzymes were observed. LPS-mediated HK activation was not sufficient to increase glycolytic flux as indicated by reduced or unchanged pyruvate and lactate levels in the renal cortex. LPS-induced HK activation was associated with increased glucose-6-phosphate dehydrogenase activity but not glycogen production. Mechanistically, LPS-induced HK activation was attenuated by pharmacological inhibitors of the EGF receptor (EGFR) and Akt, indicating that EGFR/phosphatidylinositol 3-kinase/Akt signaling is responsible. Our findings reveal LPS rapidly increases renal cortical HK activity in an EGFR-and Akt-dependent manner and that HK activation is linked to increased pentose phosphate pathway activity.lipopolysaccharide; acute kidney injury; hexokinase; EGFR; pentose phosphate pathway ACUTE KIDNEY INJURY (AKI) is defined as an abrupt decline in renal function which occurs over a period of hours to days (7). A number of stimuli may lead to the development of AKI, including sepsis, ischemia-reperfusion (I/R) injury, trauma, or exposure to nephrotoxic agents. Among the leading causes of AKI, sepsis is thought to be the most common contributor (ϳ50% of all cases) in the intensive care unit (ICU) setting (64). Despite increased understanding of the pathophysiology underlying AKI, mortality from the disease remains near 40% and has not changed over several decades (27,60,65). AKI in the setting of sepsis increases this mortality by almost twofold (48, 65). Unfortunately, currently available treatments for sepsis-induced AKI include supportive care and renal replacement therapy. A better understanding of the mechanisms leading to renal damage as well as recovery in septic AKI is essential for development of therapeutic strategies to improve outcomes in this disease.The pathophysiology of sepsis-induced AKI is widely recognized as multifactorial, involving microvascular, immunological, and tubular components that contribute to renal dysfunction. The microvascular component is characterized by reduced capillary flow, leading to local areas of hypoperfusion (29,30,66). Infiltration of both macrophages and neutrophils also exposes the septic ki...

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“…The PI3Ks are a conserved family of signal transduction enzymes that are involved in cellular activation, inflammatory responses, chemotaxis, and proliferation [39,46]. Furthermore, PI3K/Akt have been shown to be downstream components of EGFR activated by different stimuli in various cell types [47,48]. This was confirmed by our observations that thrombin-induced MMP-9 expression and Akt phosphorylation was reduced by the inhibitors of EGFR (AG1478), PI3K (LY294002), and Akt (SH-5), consistent with the results indicating that PI3K/Akt were necessary for angiotensin II-induced MMP-9 expression in breast cancer cells [49].…”

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“…EGFR activation is required for renal regeneration and functional recovery after AKI. Smith et al (18) demonstrated that EGF signaling pathway is activated in a mouse model of sepsis-induced AKI. Chen et al (19) reported lower urine EGF levels in infants with severe perinatal asphyxia compared with controls, suggesting that EGF may play a role in the repair of acute renal injury after asphyxia.…”

Metabolic reprogramming and tolerance during sepsis-induced AKI

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