title: Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.
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 (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.
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Renal Division, James J Peters Bronx VA Medical Center, Bronx, New York, United States of America.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Leventhal
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Ni
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Morgan
authors.initials: M
authors.lastname: Osmond
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: G Luca
authors.initials: GL
authors.lastname: Gusella
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Fadi
authors.initials: F
authors.lastname: Salem
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Renal Division, James J Peters Bronx VA Medical Center, Bronx, New York, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ross
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D019446:Endotoxemia / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines