title: Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury.
abstract: The proximal straight tubule (S3 segment) of the kidney is highly susceptible to ischemia and toxic insults but has a remarkable capacity to repair its structure and function. In response to such injuries, complex processes take place to regenerate the epithelial cells of the S3 segment; however, the precise molecular mechanisms of this regeneration are still being investigated. By applying the "toxin receptor mediated cell knockout" method under the control of the S3 segment-specific promoter/enhancer, Gsl5, which drives core 2 β-1,6-N-acetylglucosaminyltransferase gene expression, we established a transgenic mouse line expressing the human diphtheria toxin (DT) receptor only in the S3 segment. The administration of DT to these transgenic mice caused the selective ablation of S3 segment cells in a dose-dependent manner, and transgenic mice exhibited polyuria containing serum albumin and subsequently developed oliguria. An increase in the concentration of blood urea nitrogen was also observed, and the peak BUN levels occurred 3-7 days after DT administration. Histological analysis revealed that the most severe injury occurred in the S3 segments of the proximal tubule, in which tubular cells were exfoliated into the tubular lumen. In addition, aquaporin 7, which is localized exclusively to the S3 segment, was diminished. These results indicate that this transgenic mouse can suffer acute kidney injury (AKI) caused by S3 segment-specific damage after DT administration. This transgenic line offers an excellent model to uncover the mechanisms of AKI and its rapid recovery.
authors: Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors: Michiko
authors: M
authors: Sekine
authors: Toshiaki
authors: T
authors: Monkawa
authors: Ryuji
authors: R
authors: Morizane
authors: Kunie
authors: K
authors: Matsuoka
authors: Choji
authors: C
authors: Taya
authors: Yoshiko
authors: Y
authors: Akita
authors: Kensuke
authors: K
authors: Joh
authors: Hiroshi
authors: H
authors: Itoh
authors: Matsuhiko
authors: M
authors: Hayashi
authors: Yoshiaki
authors: Y
authors: Kikkawa
authors: Kenji
authors: K
authors: Kohno
authors: Akemi
authors: A
authors: Suzuki
authors: Hiromichi
authors: H
authors: Yonekawa
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D004167:Diphtheria Toxin / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase