Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression

Jeremy S. Leventhal, Jie Ni, Morgan Osmond, Kyung Lee, G. Luca Gusella, Fadi Salem, Michael J. Ross

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hrBUN 100.1mg/dl +/- 14.8vs54.6mg/dl +/-11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.

Original languageEnglish (US)
Article numbere0150001
JournalPLoS One
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Fingerprint

autophagy
Autophagy
kidney cells
Acute Kidney Injury
epithelial cells
cytokines
Epithelial Cells
kidneys
Cytokines
Kidney
Lipopolysaccharides
lipopolysaccharides
Cell signaling
mice
Sepsis
Wounds and Injuries
injection
Endotoxins
proximal tubules
Interleukin-6

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. / Leventhal, Jeremy S.; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G. Luca; Salem, Fadi; Ross, Michael J.

In: PLoS One, Vol. 11, No. 3, e0150001, 01.03.2016.

Research output: Contribution to journalArticle

Leventhal, Jeremy S. ; Ni, Jie ; Osmond, Morgan ; Lee, Kyung ; Gusella, G. Luca ; Salem, Fadi ; Ross, Michael J. / Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. In: PLoS One. 2016 ; Vol. 11, No. 3.
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