title: Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.
abstract: The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury.
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kotani
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyao
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kawai
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Leila
authors.initials: L
authors.lastname: Jemail
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Abiru
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D003094:Collagen / Q000737:chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D007249:Inflammation; D007668:Kidney; D007674:Kidney Diseases / Q000150:complications / Q000503:physiopathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008107:Liver Diseases / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D018384:Oxidative Stress; D011725:Pyridines / Q000633:toxicity
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D011725:Pyridines; D003094:Collagen