TY - JOUR
T1 - Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression
AU - Leventhal, Jeremy S.
AU - Ni, Jie
AU - Osmond, Morgan
AU - Lee, Kyung
AU - Gusella, G. Luca
AU - Salem, Fadi
AU - Ross, Michael J.
N1 - Funding Information:
This research was supported by the NIH/NIDDK grant R01 DK101338 and DK108346 (M.R.) and an NIH/NIDDK K08 DK090217 (J.S.L). Microscopy was performed at the Microscopy CORE at the Icahn School of Medicine at Mount Sinai.
PY - 2016/3
Y1 - 2016/3
N2 - 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.
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 (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.
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U2 - 10.1371/journal.pone.0150001
DO - 10.1371/journal.pone.0150001
M3 - Article
C2 - 26990086
AN - SCOPUS:84962204197
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 3
M1 - e0150001
ER -