title: Apoptosis of the thick ascending limb results in acute kidney injury.
abstract: Ischemia- or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans.
authors.affiliation: Veterans Administration Hospital, Department of Medicine/Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA. manakan.b.srichai@vanderbilt.edu
authors.forename: Manakan B
authors.initials: MB
authors.lastname: Srichai
authors.forename: Chuanming
authors.initials: C
authors.lastname: Hao
authors.forename: Linda
authors.initials: L
authors.lastname: Davis
authors.forename: Anastasia
authors.initials: A
authors.lastname: Golovin
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.forename: Steve
authors.initials: S
authors.lastname: Dunn
authors.forename: Nada
authors.initials: N
authors.lastname: Bulus
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D000998:Antiviral Agents; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015774:Ganciclovir; D015870:Gene Expression; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism; D008138:Loop of Henle / Q000293:injuries* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009088:Mucoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D058949:Uromodulin
chemical_list: D000998:Antiviral Agents; D009088:Mucoproteins; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D013937:Thymidine Kinase; D015774:Ganciclovir