title: Maladaptive proximal tubule repair: cell cycle arrest.
abstract: Acute kidney injury (AKI) leads to worsening of chronic kidney disease (CKD), and CKD predisposes to the clinical entity of AKI. The tubules of the kidney play a central role in the fibrotic response, which ultimately leads to progressive kidney disease. The cellular mechanisms responsible for the epidemiological association between AKI and CKD are complex. In order to unravel characteristics of this direct involvement of the tubules, in particular the proximal tubules, we established a model to specifically target injury to the proximal tubule using a genetic approach to express the simian diphtheria toxin (DT) receptor in the proximal tubule. A single administration of DT to the proximal tubule resulted in inflammation, reversible injury, and adaptive repair. By contrast, thrice repeated injury led to maladaptive repair with sustained tubule injury, vascular rarefaction, proliferation of interstitial myofibroblasts, interstitial fibrosis, and glomerular sclerosis. An important feature of the maladaptive repair process after severe injury is the development of cell cycle arrest in G2/M. There is a subsequent activation of the DNA repair response with activation of a secretory phenotype whereby profibrotic factors are released. This insight introduces a number of potential new targets for therapeutic intervention to prevent and/or arrest CKD progression.
authors.affiliation: Renal Division and Biomedical Engineering Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass., USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004260:DNA Repair; D004167:Diphtheria Toxin / Q000633:toxicity; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000473:pathology; D005355:Fibrosis; D016195:G2 Phase; D020869:Gene Expression Profiling; D005813:Genes, Synthetic; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000098:blood supply; D007678:Kidney Glomerulus / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008677:Metaphase; D051379:Mice; D058990:Molecular Targeted Therapy; D012038:Regeneration; D051436:Renal Insufficiency, Chronic / Q000150:complications; D017582:Renal Replacement Therapy; D015427:Reperfusion Injury / Q000503:physiopathology
chemical_list: D002843:Chromatin; D016207:Cytokines; D004167:Diphtheria Toxin; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins