title: ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction.
abstract: Inflammation plays a crucial role in the pathophysiological characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a multiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X7-potassium efflux and reactive oxygen species-dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Department of Nephrology, Jichi Medical University, Tochigi, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Komada
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Usui
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Koumei
authors.initials: K
authors.lastname: Shirasuna
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.affiliation: Department of Cardiovascular Medicine and Translational Systems Biology and Medicine Initiative, the University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Nagano, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.affiliation: Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Nagano, Japan.
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.affiliation: Department of Nephrology, Jichi Medical University, Tochigi, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.affiliation: Department of Nephrology, Jichi Medical University, Tochigi, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.affiliation: Department of Nephrology, Jichi Medical University, Tochigi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
authors.affiliation: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan. Electronic address: masafumi2@jichi.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D007249:Inflammation / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D014517:Ureteral Obstruction / Q000150:complications* / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; C498534:Pycard protein, mouse