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

• Published in: American journal of physiology. Renal physiology Vol. 307; no. 4; pp. F435 - F444
• Main Authors: Smith, Joshua A, Stallons, L Jay, Schnellmann, Rick G
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.08.2014
• Subjects: Acute Kidney Injury - physiopathology; Animals; Enzyme Activation - drug effects; Enzymes; Glucosephosphate Dehydrogenase - metabolism; Glycolysis - drug effects; Heterocyclic Compounds, 3-Ring - pharmacology; Hexokinase - metabolism; Kidney Cortex - drug effects; Kidney Cortex - physiology; Kidney diseases; Kinases; Lipopolysaccharides; Male; Mice; Pentose Phosphate Pathway - physiology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - physiology; Sepsis; Signal transduction; Toxins; acute kidney injury; lipopolysaccharide; EGFR; pentose phosphate pathway; hexokinase
• ISSN: 1931-857X; 1522-1466
• 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 (∼2-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.