title: Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury.
abstract: 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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and.
authors.forename: L Jay
authors.initials: LJ
authors.lastname: Stallons
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina schnell@musc.edu.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000502:physiology*; D000077156:Gefitinib; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006593:Hexokinase / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D008070:Lipopolysaccharides; C548887:MK 2206; D011799:Quinazolines; D005954:Glucosephosphate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; C515658:HK1 protein, mouse; D006593:Hexokinase; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: EGFR; acute kidney injury; hexokinase; lipopolysaccharide; pentose phosphate pathway