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. 2014 Aug 15;307(4):F435-44. doi: 10.1152/ajprenal.00271.2014. Epub 2014 Jul 2.

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.

Keywords: EGFR; acute kidney injury; hexokinase; lipopolysaccharide; pentose phosphate pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / physiopathology*
  • Animals
  • Enzyme Activation / drug effects
  • ErbB Receptors / physiology*
  • Gefitinib
  • Glucosephosphate Dehydrogenase / metabolism
  • Glycolysis / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Hexokinase / metabolism*
  • Kidney Cortex / drug effects
  • Kidney Cortex / physiology*
  • Lipopolysaccharides
  • Male
  • Mice
  • Pentose Phosphate Pathway / physiology*
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / pharmacology

Substances

  • Heterocyclic Compounds, 3-Ring
  • Lipopolysaccharides
  • MK 2206
  • Quinazolines
  • Glucosephosphate Dehydrogenase
  • Phosphatidylinositol 3-Kinases
  • HK1 protein, mouse
  • Hexokinase
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Gefitinib