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

Joshua A. Smith, L. Jay Stallons, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)F435-F444
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number4
DOIs
StatePublished - Aug 15 2014
Externally publishedYes

Keywords

  • Acute kidney injury
  • EGFR
  • Hexokinase
  • Lipopolysaccharide
  • Pentose phosphate pathway

ASJC Scopus subject areas

  • Physiology
  • Urology

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