title: Interacting roles of myofibroblasts, apoptosis and fibrogenic growth factors in the pathogenesis of renal tubulo-interstitial fibrosis.
abstract: The interrelationship between myofibroblasts and fibrogenic growth factors in the pathogenesis of renal fibrosis is poorly defined. A temporal and spatial analysis of myofibroblasts, their proliferation and death, and presence of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-B (PDGF-B) was carried out in an established rodent model in which chronic renal scarring and fibrosis occurs after healed renal papillary necrosis (RPN), similar to that seen with analgesic nephropathy. Treated and control groups (N = 6 and 4, respectively) were compared at 2, 4, 8 and 12 weeks. A positive relationship was found between presence of tubulo-interstitial myofibroblasts and development of fibrosis. Apoptotic myofibroblasts were identified in the interstitium and their incidence peaked 2 weeks after treatment. Levels of interstitial cell apoptosis and fibrosis were negatively correlated over time (r = -0.57, p < 0.01), suggesting that as apoptosis progressively failed to limit myofibroblast numbers, fibrosis increased. In comparison with the diminishing apoptosis in the interstitium, the tubular epithelium had progressively increasing levels of apoptosis over time, indicative of developing atrophy of nephrons. TGF-beta1 protein expression had a close spatial and temporal association with fibrosis and myofibroblasts, whilst PDGF-B appeared to have a closer link with populations of other chronic inflammatory cells such as infiltrating lymphocytes. Peritubular myofibroblasts were often seen near apoptotic cells in the tubular epithelium, suggestive of a paracrine toxic effect of factor/s secreted by the myofibroblasts. In vitro, TGF-beta1 was found to be toxic to renal tubular epithelial cells. These findings suggest an interaction between myofibroblasts, their deletion by apoptosis, and the presence of the fibrogenic growth factor TGF-beta1 in renal fibrosis, whereby apoptotic deletion of myofibroblasts could act as a controlling factor in progression of fibrosis.
authors.affiliation: Department of Pathology, School of Medicine, University of Queensland, Herston Road, Herston, Brisbane 4006, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Lane
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.forename: Betty
authors.initials: B
authors.lastname: Pat
authors.forename: Clay
authors.initials: C
authors.lastname: Winterford
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Endre
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005355:Fibrosis; D006133:Growth Substances / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology*; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta