PMID- 26990086
OWN - NLM
STAT- MEDLINE
DCOM- 20160728
LR  - 20190219
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 3
DP  - 2016
TI  - Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular 
      Epithelial Cell Cytokine Expression.
PG  - e0150001
LID - 10.1371/journal.pone.0150001 [doi]
LID - e0150001
AB  - 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 (24hr BUN 
      100.1mg/dl +/- 14.8 vs 54.6mg/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.
FAU - Leventhal, Jeremy S
AU  - Leventhal JS
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
AD  - Renal Division, James J Peters Bronx VA Medical Center, Bronx, New York, United 
      States of America.
FAU - Ni, Jie
AU  - Ni J
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
FAU - Osmond, Morgan
AU  - Osmond M
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
FAU - Lee, Kyung
AU  - Lee K
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
FAU - Gusella, G Luca
AU  - Gusella GL
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
FAU - Salem, Fadi
AU  - Salem F
AD  - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, United States of America.
FAU - Ross, Michael J
AU  - Ross MJ
AD  - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, New York, United States of America.
AD  - Renal Division, James J Peters Bronx VA Medical Center, Bronx, New York, United 
      States of America.
LA  - eng
GR  - K08 DK090217/DK/NIDDK NIH HHS/United States
GR  - R01 DK101338/DK/NIDDK NIH HHS/United States
GR  - R01 DK108346/DK/NIDDK NIH HHS/United States
GR  - DK108346/DK/NIDDK NIH HHS/United States
GR  - NIDDK K08 DK090217/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160318
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
SB  - IM
MH  - Acute Kidney Injury/complications/*immunology/metabolism
MH  - Animals
MH  - *Autophagy
MH  - Cell Line
MH  - Cytokines/*metabolism
MH  - Endotoxemia/complications/*immunology/metabolism
MH  - Epithelial Cells/metabolism
MH  - Kidney Tubules/*metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
PMC - PMC4798771
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/03/19 06:00
MHDA- 2016/07/29 06:00
PMCR- 2016/03/18
CRDT- 2016/03/19 06:00
PHST- 2015/10/25 00:00 [received]
PHST- 2016/02/08 00:00 [accepted]
PHST- 2016/03/19 06:00 [entrez]
PHST- 2016/03/19 06:00 [pubmed]
PHST- 2016/07/29 06:00 [medline]
PHST- 2016/03/18 00:00 [pmc-release]
AID - PONE-D-15-46791 [pii]
AID - 10.1371/journal.pone.0150001 [doi]
PST - epublish
SO  - PLoS One. 2016 Mar 18;11(3):e0150001. doi: 10.1371/journal.pone.0150001. 
      eCollection 2016.