title: TLR9 Mediates Remote Liver Injury following Severe Renal Ischemia Reperfusion.
abstract: Ischemia reperfusion injury is a common cause of acute kidney injury and is characterized by tubular damage. Mitochondrial DNA is released upon severe tissue injury and can act as a damage-associated molecular pattern via the innate immune receptor TLR9. Here, we investigated the role of TLR9 in the context of moderate or severe renal ischemia reperfusion injury using wild-type C57BL/6 mice or TLR9KO mice. Moderate renal ischemia induced renal dysfunction but did not decrease animal well-being and was not regulated by TLR9. In contrast, severe renal ischemia decreased animal well-being and survival in wild-type mice after respectively one or five days of reperfusion. TLR9 deficiency improved animal well-being and survival. TLR9 deficiency did not reduce renal inflammation or tubular necrosis. Rather, severe renal ischemia induced hepatic injury as seen by increased plasma ALAT and ASAT levels and focal hepatic necrosis which was prevented by TLR9 deficiency and correlated with reduced circulating mitochondrial DNA levels and plasma LDH. We conclude that TLR9 does not mediate renal dysfunction following either moderate or severe renal ischemia. In contrast, our data indicates that TLR9 is an important mediator of hepatic injury secondary to ischemic acute kidney injury.
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Bakker
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Angelique M
authors.initials: AM
authors.lastname: Scantlebery
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Loes M
authors.initials: LM
authors.lastname: Butter
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Gwendoline J D
authors.initials: GJ
authors.lastname: Teske
authors.affiliation: Center of Experimental & Molecular Medicine, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands; Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Jaklien C
authors.initials: JC
authors.lastname: Leemans
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002460:Cell Line; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase